Current Topics in Medicinal Chemistry

Peptides represent an integral part of biological systems across organisms, as they are well-suited to the signal transduction paradigms required for life. Moreover, peptides are ubiquitous in medicine and represent a growing number of drug development programs. Conformational flexibility, relative ease of synthesis, and affordable cost are responsible for historical interest in peptide therapeutics. Use of linear peptides may be limited by their inadequate stability and membrane permeability. Recent emphasis has turned to peptidomimetics (modified peptides), such as cyclic peptides, which with improved methods for synthesis and modification afford greater stability and thus selectivity and bioavailability compared to linear peptides. These advances have ignited programs employing peptidomimetics with improved drug properties for targeting sought after protein-protein interactions (PPIs) dysregulated in many diseases, which were previously considered undruggable by small molecules due to their large interaction surfaces. Included in this thematic issue are six articles exploring timely aspects of peptides in physiology, medicinal chemistry and drug development, with particular emphasis on peptidomimetics and their application to PPI targets. Lerner, Hanout, Ben-Uliel, Gani, Leshem, and Qvit review endogenous peptides with emphasis on the cardiovascular system and focus on the role of natriuretic peptides cardiovascular disease and associated drug discovery [1]. Sirhan and Piran discuss the multifaceted roles of peptides in glucose homeostasis and diabetes mellitus pathophysiology, illustrating the many peptide hormones that mediate these processes and the numerous peptide modulators for used or being evaluated for therapeutic management of diabetes mellitus [2]. Next, Garcia, Arranz- Gibert, Sánchez-Navarro, Giralt, and Teixidó review current modalities of gene therapy and gene delivery to the brain and central nervous system (CNS), highlighting the promising role of peptides as potential gene delivery vectors [3]. Feijtel, de Jong, and Nonnekens examine the development and current use of peptide receptor radionuclide therapy and its important role in treatment of cancer, as well as ongoing efforts and opportunities to further improve its efficacy. Pivoting slightly to the growing number of microbialderived and human host-derived antimicrobial peptides (AMPs) [4], Rubin and Qvit present the diverse collection AMPs, their interactions with the human immune system, their antineoplastic activities, their roles in modulating PPIs for cancer therapy, and how AMPs may be further harnessed using novel peptide modification technologies [5]. Lastly, Dang and Wang discuss newly discovered AMPs, their relevance to addressing emergent challenges of antibiotic resistant pathogens, and other potential therapeutic applications [6]. We thank the journal for the opportunity to prepare this timely issue, and we thank the readers for their dedicated interest. We hope that the material is engaging and useful for further study and application.

Since the dawn of history, opium has been used as an analgesic, antidiarrheal, and for the treatment of other ailments. Despite tragic experiences, including the Opium War, the opioid analgesics, such as morphine, oxycodone, oxymorphone, and fentanyl, are used even now as mainstay analgesics in humans. The opioid analgesics exhibit profound antinociceptive effects, as well as several side effects, including constipation, respiratory depression, vomiting, and drug dependence. Extensive efforts have been made to reduce or eliminate these side effects, but it is difficult to say that fruitful results have been achieved. Recent circumstances related to the “opioid crisis” necessitate the development of much safer analgesics. Many researchers are seeking ideal analgesics based on current scientific knowledge. This thematic issue deals with current topics in the opioid field, mainly in seeking ideal analgesics or the reduction of side effects. The first topic is “The G Protein Signal-Biased Compound TRV130; Structures, Its Site of Action and Clinical Studies,” by Yasuhito Uezono and colleagues, which deals with oliceridine (TRV130), which is a G-protein biased μ receptor agonist developed by Trevena, Inc., in the United States. They describe not only the drug discovery campaign, but also the synthesis, site of action, and clinical studies [1]. The second review article, by Masanao Inagaki and co-workers, is entitled, “Naldemedine: Peripherally Acting Opioid Receptor Antagonist for Treating Opioid-induced Adverse Effects.” Naldemedine, which was developed by Shionogi Co., Ltd., in Japan, is a peripherally acting μ and δ receptor dual antagonist that was launched in Japan, the United States, and the European Union to treat opioid-induced constipation. They discuss the structure-activity relationship, large-scale synthesis, and clinical trials [2]. The third article by Wakako Fujita is “Aiming at Ideal Therapeutics-MOPr/DOPr or MOPr-DOPr Heteromer-targeting Ligand.” The heterodimeric opioid receptors among μ, δ, and κ receptors are promising targets. Fujita focuses on the μ-δ heteromers and discusses the ligands interacting with them and their pharmacological effects [3]. Fourth, Damian Bartuzi and colleagues provide an overview of the positive allosteric modulators (PAMs) of opioid receptors in their article entitled, “Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses.” Allosteric modulation is an interesting mechanism of action from the perspective of their spatiotemporally characteristic properties. They survey the PAMs of the opioid receptors and discuss the complexity of allosteric modulation. The synthesis of the known opioid allosteric modulators is also briefly presented [4]. In the fifth article, “Exploring μ-Opioid Receptor Splice Variants as a Specific Molecular Target for New Analgesics,” Hirokazu Mizoguchi and Hideaki Fujii review the new targets (splice variants) for novel opioid analgesics derived from a μ opioid receptor gene. The traditional μ receptor agonists (e.g., morphine and DAMGO) do not interact with the splice variants. They describe amidino-TAPA and IBNtxA, which interact with the specific μ opioid receptor splice variants, as having promising properties; they exhibit potent analgesic effects but do not have the liability of dependence [5]. Norikazu Kiguchi and co-workers describe nociceptin receptor agonists as novel analgesics in the sixth article, “Nociceptin/ Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics.” Nociceptin was named after its nociceptive effects (not antinociceptive effects). They discuss the potential analgesic agents of nociceptin receptor agonists based on experimental results in primates, including humans [6]. Finally, Shigeto Hirayama and Hideaki Fujii describe the δ receptor inverse agonists in “δ Opioid Receptor Inverse Agonists and their In Vivo Pharmacological Effects.” The inverse agonists can suppress the signals derived from the constitutive activities of the receptors. They provide a summary of both δ receptor inverse agonists and the pharmacological effects induced by such compounds [7]. I would like to thank all of the contributors in this thematic issue and the reviewers who provide suggestive comments.

Nanotechnology has great potential to overcome different limitations of the conventional diagnostic and therapeutic methods in medicine [1, 2]. Nanoparticles (NPs) have shown promising outcomes in medical imaging, radiotherapy, drug delivery and tissue engineering and bone disorders [3-5]. Nanoscale, unique physiochemical features of NPs in one hand and advances in the allied technologies such as material sciences, chemistry and engineering on the other hand have brought considerable progress in treatment and therapy in medicine. Recent advances in chemistry and material sciences in nanoscale have been dramatically exploited in medical theranostics particularly targeted drug and gene delivery strategies [5, 6]. This issue reviews recent advances in applications of NPs in targeted drug delivery for molecular imaging (MI) and treatment of different disorders. It reviews the advances in targeted drug delivery strategies in brain tumors, neurological disorders such as Parkinson’s disease (PD), and bone disorders. It discusses different targeting strategies in drug delivery including tumor microenvironment (TME), blood-brain barrier (BBB), and blood-brain tumor barrier (BBTB). Jin et al. reviewed the applications of nanomedicine in MI for early cancer diagnosis and discussed recent advances in fluorescence NPs. MI aims to characterize and quantitatively visualize the biological processes at the molecular level in living cells [7, 8]. The main element critical in the performance of any MI modality is a high affinity molecular probe that serves as the source of image contrast. This is where the nanotechnology equips MI with high performance probes. Recent advances in engineering and chemical modifications, have made it possible to develop and use NPs as MI probes [9-11]. Fluorescent NPs have shown significant potentials in optical molecular imaging. The three main groups of fluorescent NPs used in medical imaging are dye-doped, quantum dots (QDs) and upconversion NPs [7, 12, 13]. Fluorescent NPs are good candidates for drug and gene delivery, detection of the chromosomal abnormalities, labeling of DNA, and visualizing DNA replication dynamics. In recent years, developing multifunctional NPs has enabled scientists to combine diagnostic and therapeutic procedures into a single modality called theranostic. Preclinical and translational findings have demonstrated that multifunctional NPs can be used to concurrently diagnose and treat a disease in an integrated theranostic modality. Zhao et al. discussed the NPs-assisted targeting strategies used in targeted drug delivery in central nervous system (CNS) cancers. They reviewed the physiological and anatomical features of the brain tumor and the BBB and discussed the roles of specific ligands in the design of functionalized nanocarriers for targeted delivery to brain tumors. The treatment of CNS cancers is limited the lack of efficient strategies to deliver anticancer drugs across the BBB and BBTB [7, 14, 15]. BBB is a highly specialized and selective barrier that actively prevents the toxins and most of anticancer agents. Nanotechnology-assisted delivery systems offer promising strategies to penetrate the BBB and reach the brain tissue. The incorporation of anticancer agents into various nanovehicles facilitates their delivery across the BBB. Moreover, surface modifications of nanovehicles with specific ligands significantly enhance the BBB penetrating capacities of the drugs and could increase the concentration of the drugs to an effective dose for killing tumor cells. Kumar et al. discussed the characteristics and applications of exosomes for management of Parkinson’s disease (PD). PD is a prevalent and severe neurodegenerative disease affecting more than 6.1 million people worldwide. Conventional drug delivery systems have limited capacity to cross the BBB. Exosomes are biological lipid bilayer membrane vesicles produced by nearly all mammalian cells. The characteristics of vesicles are unique to their cell of origin and are primarily involved in intracellular communication. The Exosomes thanks to their nanoscale dimension can easily penetrate BBB to reach brain tissue particularly, the substantia nigra as the main target in PD treatment. Zhang et al. reviewed the fundamentals and applications of targeting strategies for modulating tumor microenvironment (TME) for cancer treatment. They reviewed the TME targeting strategies and discussed the advances in using Traditional Chinese Medicine (TCM) medications and the molecular mechanisms of several TCM herbs and their monomers on modulating the TME. TME surrounds cancer cells and plays important roles in tumor development, growth, progression, and therapy resistance. TME is a hypoxic and acidic environment that includes immune cells, pericytes, fibroblasts, endothelial cells, various cytokines, growth factors, and extracellular matrix components. Targeting TME using targeted drug delivery and nanoparticles is an attractive strategy for the treatment of solid tumors and recently has received significant research attention under precise medicine concept. TME plays a pivotal role in the overall survival and metastasis of a tumor by stimulating cell proliferation, preventing the tumor clearance by the immune cells, enhancing the oncogenic potential of the cancer cells, and promoting tumor invasion. Hepatocellular Carcinoma (HCC) is one of the major causes of cancer-associated deaths affecting millions of individuals worldwide each year. TCM herbs contain several bioactive phytoconstituents that can exert a wide range of physiological and immunological effects on the system. Several TCM herbs and their monomers have shown inhibitory effects in HCC by modulating the TME [16, 17]. One of the main domains where nanotechnologies have shown great potentials is tissue engineering and bone healing [18- 21]. Zhao et al. reviewed the applications of NPs in bone disorders and tissue engineering such as NPs-assisted osteogenic agents, nanocomposites, and scaffolds for tissue engineering and bone healing. They discussed basic and translational sciences and clinical implications of the nanotechnology in tissue engineering and bone diseases. Advances in the synthesis and design of nanomaterials along with advances in genomics and tissue engineering have been integrated for efficient management of bone healing and orthopedic technology. Porous implant substrates have been developed as bone defect augmentation and drugcarrier systems. Nanotechnology has been utilized in synthesis of scaffolds, delivery mechanisms, controlled modification of surface topography and composition, and biomicroelectromechanical systems, which are promising for bone healing and tissue engineering.

This is the second part of issue which is related to current trends in enzyme inhibition and docking analysis in drug design. The topics presented deal with characterization of Pseudomonas aeruginosa glucose 6- phosphate isomerase, analyses against M. tuberculosis enzyme targets, antimicrobial activity of isoindole-3-1,1- dioxide derivatives, docking assisted prediction of the mechanism of action of potential inhibitors of protein tyrosine phosphate (PTP1B) against type II diabetes mellitus, and extensive review on RAS inhibition as well as ATP synthase inhibitors as anti-tubercular agents. The first paper deals with glucose-6-phosphate isomerase (G6PI) which catalyses the second step in glycolysis in the reversible interconversion of the aldohexose glucose-6-phosphate, a six membered ring moiety, to the ketohexose fructose 6-phosphate five membered ring moiety. This enzyme is of utmost importance due to its multifunctional role as neuroleukin, autocrine motility factor, etc. in various species. G6PI from P. aeruginosa is less explored for its moonlighting properties which can be predicted by studying the active site conservation of residues and their interactions with specific ligands [1]. Authors studied G6PI in a self-inducible construct in a bacterial expression system with purification using Ni-NTA chromatography. The hydrogen bonds and water bridges dominating the interactions in the active site between the protein and ligand with strong affinity was identified. G6PI was successfully crystallized and the data has been collected at 6Å. The authors are focused on improving the crystal quality for obtaining higher resolution data. They have characterized the enzymatic protein in order to check the conservation of residues in the active site through wet lab and in-silico experimentation. The protein was expressed in E. coli and was analyzed for proper folding by CD spectrometry. Differential scanning fluorimetry was used to check the binding pattern of E4P with the protein. The next paper refers to the structure-based design of inhibitors against tuberculosis targets. Tuberculosis (TB) is a destructive disease responsible for millions of individual deaths worldwide and is caused by a mycobacterial organism, the tubercle bacillus or Mycobacterium tuberculosis. Although TB can be treated, cured and can be prevented if persons followed prescribed treatment, scientists have never come close to wiping it out due to a spiky rise in the incidence of multi drug-resistant (MDR) and extensively drug-resistant (XDR) mycobacterium strains. In the present study the authors review potential new tubercular target enzymes such as InhA, MmpL3, ATP synthase, DprE1, QcrB and MenA. They describe the structure-based design of the corresponding target inhibitors which are under clinical investigation to determine structural features for the discovery of new chemical entities (NCEs) with specificity towards MDR and XDR M. tuberculosis [2]. The third paper deals with docking-assisted selection of isoindole-3-1,1-dioxide derivatives, and evaluation of their antimicrobial activity and elucidation of probable mechanisms of antibacterial and antifungal activities. Thirty five 6,7- dimethoxy-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-1,1-dioxide derivatives from the InterBioScreen collection were docked to three bacterial and fungal targets, E.coli MurA, DNAG of En. cloacae and CYP 51 of C. albicans. Compounds with the best binding energy were chosen for the evaluation of activity. A group of 10 chosen compounds presented good antibacterial activity, better than the reference drugs ampicillin and streptomycin. Antifungal potential also appeared to be higher than that of the reference drugs befonazole and ketoconazole. In order to elucidate the probable mechanism of antibacterial activity several bacterial drug targets were used for docking analysis. In particular, the enzymes involved in cell membrane peptidoglycan biosynthesis, Mur F and Mur E, dihydrofolate reductase and the penicillin binding proteins PBP1b and PBP3 were used. The obtained results failed to explain the antibacterial activity, while according to docking analysis, the antifungal activity can be explained by the inhibition of the CYP51 enzyme for most of the compounds while antibacterial activity may depends on multiple factors [3]. The next paper refers to inhibitors of protein tyrosine phosphatase (PTP1B) as a target for type II diabetes mellitus. PTP1B is currently considered as one of the best validated biological targets for non-insulin dependent diabetic and obese individuals [4]. Several small molecule PTP1B inhibitors discussed as diaminopyrroloquinazoline, triazines, pyrimido triazine derivatives, 2-(benzylamino)-1-phenylethanols, ureas, acetamides and piperazinylpropanols, phenylsulphonamides and phenylcarboxamides, benzamido, arylcarboxylic acid derivatives, arylsufonyl derivatives, thiazoles, isothiazolidiones and thiazolodinones are considered as promising drug candidates which could be derivatized for the generation of large number of combinatorial molecules. Inhibitors containing the sulfonyl moiety, viz. sulfamic acids, sulfonic acids and sulfonamides, have shown good PTP inhibitory activity. In addition, sulfonamides are known to function as good hydrogen acceptors in biological system. So using the substructural approach, the compounds with a sulfonyl moiety can be further optimized to obtain potent PTP inhibitors. Several approaches mentioned to improve cell permeability, such as based on the reduction of the number of negative charges to enhance the lipophillic character, may favor the transportation of the ligand to the target, thus reducing the hydrophilic character of the pTyr mimetics with negative charges. The approaches based on the ligand, substructure or fragments and/or structure-based approaches utilizing the co-crystal structures of PTP1B used in designing new prototypes are showing high potentials. The next paper deals with inhibition of RAS which is often mutated in most of the human cancers. This review paper describes the role of RAS in cancer drug discovery, the diverse methodologies used to develop direct or indirect RAS inhibitors, and current accomplishments in the progress of novel RAS inhibitors, RAS structure, RAS mutation, or the RAS pathway as well as different strategies for targeting RAS are discussed. Among the strategies discussed are targeting Ras membrane localization, prevention of RAS-GTP formation, targeting downstream signaling regulators and inhibition of mutant specific RAS. As a future perspective, the authors mentioned the advancement of a covalent inhibitor or a combinatorial approach with a RAS mediated pathway to achieve high selectivity and eradicate off-target toxicity [5]. The last paper refers to ATP synthase inhibitors as anti-tubercular agents. Tuberculosis (TB) has been a worldwide pandemic disease of the past and has returned with more problems and complexities. The global emergence of MDR-TB and XDRTB cases is currently of great concern. Identification of the effective target ATPase has led medicinal chemists to develop novel potent molecules because of the well acceptance of bedaquiline (TMC-207) for the treatment of MDR-TB. A set of 25 molecules and TMC-207 analogues were evaluated under similar conditions in the same laboratory were used in the development of QSAR models. The developed QSAR model has predictive value as evidenced by a high correlation between the observed and predictive pIC50 values in the test set molecules. The QSAR model indicates that the MR descriptor is the most important positive contributor for activity because of its high regression coefficient value and statistical significance as compared to negatively contributing PC and CMA parameters [6]. A pharmacophore model was created, developed for the antitubercular activity. Thise M. tuberculosis H37Rv QSAR model showed a high correlation and described a similar dependence on the same descriptors. It unambiguously confirms that ATP Synthase is the target enzyme for the antitubercular activity of these molecules. It should be mentioned that the developed QSAR models both for ATP Synthase inhibition and antitubercular activity against the M. tuberculosis H37Rv strain may be useful not only to improve the activity in the series taken for the development of the model but also for virtual screening of the focused chemical libraries.

The main mission of medicinal chemistry is the understanding of molecular reasons for the activity of a drug or drug candidate. Different strategies and approaches could be used to achieve the molecular design of new structures, such as the concept of privileged scaffolds. This strategy was to construct high-affinity ligands from core structures that can bind to one or more receptors. Privileged scaffold-based design has evolved from a stand-alone technology to an integral component of various lead generation platforms. The review entitled “Synthesis and Biological Activity Study of Tanshinone Derivatives: A Literature and Patent Review” focused on the important scaffold tanshinone which is a group of lipophilic components isolated from danshen and containing abietane, a diterpenoid quinone [1]. Considering the fact that thiazole is an important organic heterocyclic compound found in many bioactive molecules and natural products in the field of medicinal chemistry, Zhang and co-authors prepared a review covering related literature in the past 20 years which reported the 2,4,5-trisubstituted thiazoles as privileged scaffolds in drug design and activity improvement [2]. Flavonoids, as natural polyphenol compounds, are mostly derived from plants, and exhibit various biological activities such as anti-inflammatory, antioxidant, and anti-tumor activities [3]. The antiinflammatory activities and mechanisms of flavonoids and their derivatives reported all over the world in recent ten years had been reviewed. For cancer treatment, quinoline and isoquinoline derivatives have shown their possibilities to work as antitumor agents in anticancer treatment. The review in our issue has described the current scenario of quinoline and isoquinoline derivatives as antitumor agents and refined the path of these derivatives to find and develop new drugs against the evil known as cancer, which is really important and meaningful [4]. Coincidentally, another review entitled “Berberine: a Promising Natural Isoquinoline Alkaloid for Development of Hypolipidemic Drug” also focused on the isoquinoline scaffold, providing insights into the deficiencies of berberine in the study of lipid-lowering drugs, and based on current state of the field, some proposals are put forward [5].

Nanotechnology along with the allied technologies have brought revolutionary advances to different fields of medicine including diagnosis and therapy [1, 2]. Recent advances in chemistry and material sciences in nanoscale have been dramatically exploited in medical theranostics particularly targeted drug and gene delivery strategies [3, 4]. Nanosystems possess extraordinary physicochemical and biological features that have shown various potentials for developing efficient cellular and molecular drug delivery techniques. The ideal features of a drug delivery system are a long circulation time, low immunogenicity, good biocompatibility, selective and specific targeting, and high penetrating ability against different barriers including vascular endothelium and blood-brain barrier. Nanochemistry is the pivotal aspect in developing such techniques. Nanochemistry, defined as the interface of chemistry and nanoscience, deals with synthesis, modifications and optimization of building blocks with different functions and biological features. These features depend on size, surface, shape and defect properties. Nanoparticles (NPs) synthesized by different techniques could improve therapeutic efficacy and diagnostic values of different conventional approaches [5, 6]. This issue aims to review the recent advances in cellular and molecular targeted drug delivery focusing on nanochemistry. The main objective of nanotechnology in medicine is developing nanosystems with high selectivity and specificity for theranostics. To achieve this, different encapsulation and conjugation strategies along with surface functionalization techniques have been developed [7, 8]. NPs for in vivo applications should overcome different barriers at system, organ, and the cellular level. To do so, different strategies during the synthesis and functionalization of NPs should be adapted. Pharmacokinetics and cellular uptake of NPs are largely associated with physicochemical attributes of NPs, morphology, hydrodynamic size, charge, and other surface properties. These properties can be adjusted during different phases of synthesis and functionalization of the NPs. Lu et al. reviewed recent advances in applications of multifunctional NPs in precise cancer treatment and discussed considerations in design and functionalization of nanocarriers. They discussed recent advances and challenges in designing different classes of multifunctional NPs for targeted drug delivery in cancer managements. Lan et al. reviewed recent advances and clinical perspectives in nanotechnology assisted chemotherapeutic approaches for targeted cancer treatment. They discussed applications of NPs-assisted chemotherapy in preclinical and clinical settings and recent advances in design and synthesis of different nanocarriers for chemotherapeutic agents. Moreover, they reviewed physicochemical features of different nanocarriers and their impacts on different tumor targeting strategies and effective parameters for efficient targeted drug delivery. They also reviewed the currently approved NPs-assisted chemotherapeutic agents for clinical applications and under different phases of clinical trials. Matrix metalloproteinases (MMPs) due to great potentials in degradation of extracellular matrix offer significant capacities in targeting of bioactive and imaging agents in cancer treatment [9, 10]. MMPs could provoke epithelial to mesenchymal transition of cancer cells and manipulate their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Therefore, targeting and particularly inhibiting MMPs within tumor microenvironment is an effective strategy for cancer treatment. Developing selective inhibitors against specific MMPs is an effective strategy for cancer treatment. Wang et al. reviewed applications and recent progresses in using MMPs in targeted drug delivery for cancer treatment and presented a new method for synthesis of a potent and highly selective inhibitor against MMP-7. Extracellular vesicles (EVs) are membrane vesicles (MVs) that play crucial roles in cell-to-cell signaling and transmitting molecular signals to adjacent as well as distant cells [11, 12]. The preserved cell membrane characteristics in MVs derived from live cells, give them great potential in biological applications. In intercellular communications, EVs serve as nanocarriers for a wide range of endogenous cargo molecules, such as RNAs, lipids, proteins, and carbohydrates. The cell-derived giant MVs can efficiently encapsulate therapeutic drugs and deliver them to target cells through membrane fusion process to synergize photothermal treatment under light exposure. Various methods have been employed to load therapeutic agents into EVs, and additional modification strategies have been employed to prolong circulation and improve targeting. Zhang et al. reviewed the recent advances in membrane derived vesicles as biomimetic vehicles for targeted drug and gene delivery systems. They discussed biological, pharmacokinetics and physicochemical characteristics, isolation techniques, engineering, and drug loading strategies of EVs. Moreover, recent preclinical and clinical progresses in applications of EVs and oncolytic virus therapy based on EVs, the clinical challenges and perspectives were discussed. Huang et al. presented a new method for synthesis of glycyrrhetinic acid and TAT peptide modified dual-functional liposome NPs for treatment of hepatocellular cancer. They developed a novel liposomal NPs using the thin-film dispersion method to encapsulate 10-hydroxycamptothecin modified with glycyrrhetinic acid and TAT peptide (GA/TAT-HCPT-LP) and assessed the in vitro and in vivo antitumor activities of the dual functional liposomal NPs. They showed that the dual modified GA/TAT can enhance tumor targeting and tumor penetration. Metal NPs are widely used in targeted therapy and diagnosis, but they are associated with toxicity that can lead to severe adverse health effects. Gao et al. presented a study investigating the quantitative structure-activity relationships to assess the toxicity of metal NPs. They used theoretical calculations and quantitative structure-activity relationships in a multiple linear regression model to investigate the relationships between the toxicity and structures of metal NPs. The study confirmed that the quantitative structure-activity relationship was a reasonable method for predicting the toxicity and designing the structures with low toxicity of metal NPs.

As already mentioned in Part 1 of this thematic issue, neurodegenerative diseases (NDs) impair memory, cognition, and movement, but currently none of them is curable, and the treatments available only manage the symptoms or halt the progression of the disease. NDs include Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS). None of these diseases unfortunately are, so far, perfectly curable and therefore the situation warrants that serious attention be paid towards the deeper studies on them. In order to move ahead in this direction, it was therefore essential that an overall development on the topic be presented, and hence a thematic issue was proposed. Now one part of this thematic issue has already been brought out containing 5 excellent articles and this Part 2 contains another 3 excellent articles, equally interesting. Of all the NDs, Alzheimer’s Disease (AD) has been more common and thus extensively studied. Therefore, in Part 1 of this thematic issue, while Gupta and Patil had presented a detail of progress on the development of anti-AD drugs, Kabir et al. had focused on the development of vaccine for it. However, now in Part 2, Uddin et al. have stressed that available therapeutic approaches cannot prevent cognitive impairment associated with AD, since the actual cause of AD is yet to be fully revealed. However, in article 1 entitled “Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease” Uddin et al. discussed the role of protein misfolding in the generation of AD. According to these authors, the continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. Protein misfolding, in fact, may not be responsible only for AD, but it may also be related to other neurodegenerative diseases, i.e., Parkinson’s disease, Huntington’s disease, multiple sclerosis and amyotrophic lateral sclerosis [1]. Shifting from AD, Deeb and Nabulsi have focused on the cause and remedy of two other neurodegenerative diseases, i.e., MS (multiple sclerosis) and ALS (amyotrophic lateral sclerosis) and thus in article 2 entitled "Exploring Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) as Neurodegenerative Diseases and Their Treatments: A Review Study”, these authors, while discussing the causes of these diseases, have pointed out that a myriad of treatments is available now for MS and that for ALS few medications that slow down disease progression are present and further input should be directed towards creating new drugs and stem cells trials. Another disease, schizophrenia, though directly not related to NDs, is a severe mental disorder that affects more than 1% of the population worldwide [2]. Therefore, in the last article of this issue entitled as “Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia”, Al-Nema and Gaurav have thrown some light on cause and remedy of this disease also. In the article it has been indicated that, though the aetiology and pathophysiology of the schizophrenia remain unclear, phosphodiesterases (PDEs) constitute the good target for the development of drugs against this mental disorder [3]. Thus, all these articles appear to be very informative and useful for further advancement in research on neurodegenerative diseases. I have greatly enjoyed reading all these articles and hope so will do the readers.

The series began with several special issues edited by many researchers worldwide and co-edited/supervised or invited by Prof. Gonzalez-Diaz H. (CTMC Enabling Tech Editor, Co-EIC, Europe Editor). The guest editors published together one editorial paper explaining the content of the issue, the relationship to other issues of the series, etc. Some of the guest editors of the first issues of the series have been: Prof. Wenjun Zhang (UC Berkeley, USA), Prof. Jia Zhou (University of Texas, USA), Prof. Ruth Nussinov (Tel Aviv Univ, Israel), Prof. William H Bisson (Oregon State University, USA), Prof. Aikaterini Lalatsa (Univ. of Portsmouth, United Kingdom), Prof. Peter Csermely (Semmelweis University, Hungary), Dr. Carlos Manlio (Díaz García (Harvard Medical School, USA), Dr. Alberto Del Rio (Italian National Research Council, Italy), Prof. Alessio Nencioni (Università degli Studi di Genova, Italy), Prof. Natalia Cordeiro (UPORTO, Portugal), Prof. Marcus T Scotti (UFPB, Brazil), ... etc. More recently, the series has been officially renamed making it easier to recognize. Since then, all editorials of the series begin with the title: “New experimental and computational tools for drug discovery”. Some of the guest editors of the renamed series have been: Prof. Massimo S. Fiandaca (UC Irvine, USA), Prof. Eugene Muratov (UNC Chapell Hill, USA), Prof. Françoise Dumas (CNRS, Univ. Paris Sud., France), Prof. Maite Sylla (CNAM, Paris), Prof. Maykel Cruz-Monteagudo (WCU, USA), Prof. Marcus Tullius Scotti (UFPB, Brazil), ... etc. The renamed series has published a total of seven special issues (1-7). The series also has its own project page on ResearchGate [CTMC Drug Discov. Series] (see this website for details, project log, and further information). The papers included in this issue follow in the same vein and can be summarized as follows: Abdmouleh et al. studied new tamoxifen derivatives. Tamoxifen citrate is a very prevalent drug marketed under several trade names like Apo-Tamox, Nolvadex, Tamec, Tamizam and Tamoplex. This molecule is approved by the U.S. FDA for breast cancer treatment. Some studies have shown that tamoxifen has anti-tuberculosis and anti-parasitic activities. Like any drug, tamoxifen possesses side effects, more or less dangerous. Basically, this work aims to first compare the antimicrobial and antitumor activities of tamoxifen and a newly synthesized tamoxifen analogue. The second aim is to determine the molecule with lesser side effects. Three groups of mice were injected with tamoxifen citrate and compound 2-(1,1-bis[4- (3dimethylaminopropoxy)phenyl]-2-phenyl-but-1-ene dihydrochloride) at doses corresponding to C1 (1/10), C2 (1/50), C3 (1/100) to the lethal dose (LD50 = 75 mg/kg) administered for adult mice. A group of not injected mice served as a study control. Experimental results suggest that compound 2 has better antitumor and antimicrobial activity than tamoxifen citrate besides its lower toxicity effects [1]. Seck et al. focused on the synthesis of 1,2,3-triazoles for the discovery of drug molecules. 1,2,3-Triazoles are obtained on a multigram scale by click chemistry in environmental conditions. As a result, 16 compounds were synthesized and evaluated in 5 microbial strains E. coli 25921, E. faecalis 29212, P. aeruginosa 27253, S. aureus 38213 and C. albicans 24433. P. aeruginosa and C. albicans were more sensitive among all the strains. They conclude that the synthesized compounds were found as potential antimicrobial agents against the Gram (+) and Gram (-) strains [2]. Esteve do Amaral et al. focused on the increasing and inappropriate use of antibiotics which has increased the number of multidrug-resistant microorganisms to these drugs, causing the emergence of infections that are difficult to control and manage by health professionals. As an alternative to combat these pathogens, some monoterpenes have harmful effects on the bacterial cell membrane, showing themselves as an alternative in combating microorganisms. Therefore, the positive enantiomer α - pinene becomes an alternative to fight bacteria, since it was able to inhibit the growth of the species Escherichia coli ATCC 25922, demonstrating the possibility of its use as an isolated antimicrobial or associated with other drugs. The aim of this study is to evaluate the sensitivity profile of the E. coli ATCC 25922 strain against clinical antimicrobials associated with (+) -α- pinene and how it behaves after successive exposures to subinhibitory concentrations of the phytochemicals. The minimum inhibitory concentration (MIC) was determined using the microdilution method. The study of the modulating effect of (+) -α- pinene on the activity of antibiotics for clinical use in strains of E. coli and the analysis of the strain's adaptation to the monoterpene were tested using the adapted disk-diffusion method. The results demonstrate that the association of monoterpene with the antimicrobials ceftazidime, amoxicillin, cefepime, cefoxitin and amikacin is positive, since it leads to the potentiation of the antibiotic effect of these compounds. It was observed that the monoterpene was able to induce cross-resistance only for antimicrobials: cefuroxime, ceftazidime, cefepime and chloramphenicol. It is necessary to obtain more concrete data for the safe use of these combinations, paying attention to the existence of possible toxic reactions related to the herbal medicine and to understand the resistance mechanisms acquired by the microorganism [3]. Viera de Oliveira et al. Ramachandran based crystallographic validation performed for the TodX protein shows that TodX critical residues can be efficiently modeled with properties of favored flexibility and acceptable crystallographic quality. The results show that the three petroleum hydrocarbons evaluated interact spontaneously with catalytic residues with very close values of free energy obtained from the three hydrocarbon / TodX complexes. Graphene nanostructures interact laterally in a different biophysical environment with FEB free energy values. In addition, the results show that the total affinity of the hydrocarbons evaluated by TodX is significantly reduced. Finally, these theoretical results open new horizons to improve bioremediation strategies towards a rational and sustainable use of nanotechnology applications based on graphene nanomaterials [4]. Ortega-Tenezaca et al. Through the PTML model it is possible to develop prediction models for large data sets. This review discusses the different uses of PTML in the area of Medicinal Chemistry, PTML models with other applications and the software available at this time for the generation of PTML models [5].

Multidrug resistance in microbes poses a major health crisis and demands for the discovery of novel antimicrobial agents. The recent pandemic of SARS-CoV-2 has raised a public health emergency in almost all the countries of the world. Unlike viruses, a bacterium plays a significant role in various environmental issues such as bioremediation. Furthermore, biosurfactants produced by various bacterial species have an edge over traditionally produced chemical surfactants for its biodegradability, low toxicity and better interfacial activity with various applications in agriculture and industry. This special issue focuses on the global perspective of drug discovery for various antimicrobial, antiviral, and antifungal agents for infectious diseases. The issue also emphasizes the ongoing developments and the role of microbes in environmental remediation. We wish the articles published in this issue will enhance the current understanding in microbiology among the readers, and serve as the "seed of an idea" for drug development for ongoing COVID-19 pandemic.

This issue is related to current trends in enzyme inhibition and docking analysis in drug design. The topics which are presented deals with neurominidase activity, DNA Topoisomerase inhibitors, ATM kinase, molecular mechanism of rare genetic disease tuberous sclerosis complex (TSC) as well as acetyl and butyrylcholinesterase inhibitors. The first paper deal with the combined in vitro and in silico studies to investigate the inhibitory activity of the anti-influenza neuraminidase (NA) and its underlying interactions of the three focused phenolic compounds caffeic acid, rosmarinic acid, and salvianolic acid. The investigation of the anti-influenza neuraminidase (NA) activity of caffeic acid and its hydroxycinnamate analogues, rosmarinic acid and salvianolic acid A was performed in comparison to a known NA inhibitor, oseltamivir. (NA) is a major glycoprotein found on the surface of the influenza virus. All-atom molecular dynamics (MD) simulations and binding free energy calculations were employed to elucidate the structural insights into the protein-ligand complexation [1]. It was found from in vitro assay that rosmarinic acid is the most potent compound with the IC50 of 0.40 μM, better than caffeic acid (IC50 of 0.81 μM) and salvianolic acid A (IC50 of >1 μM). From 100-ns MD simul tions, the ligand bindings increased the stability of NA as compared to the apoprotein, and all the simulated models entered the equilibrium state after 60-ns. All findings led to the decision that rosmarinic acid is potential lead compound for further development of a potential antiinfluenza NA inhibitor. The next paper refers to DNA Topoisomerase II enzyme as a promising anticancer treatment approach since Topo II controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription and chromosome segregation. 37 previously synthesized 2,5,6-substituted benzoxazole, benzimidazole, benzothiazole, and oxazolo(4,5-b)pyridine derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity using the Drosophila melanogaster topoisomerase IIA enzyme in a cell free system. 3D Structure of the enzyme was generated by homology modelling. Molecular docking studies were carried out with this model using two different software environments and two different methods [2]. The next paper deals with the inhibitors of ATM kinase. The inhibition of kinases of the DDR pathway is very important since cancer cells exploit these kinases for their survival leading to the development of resistance towards DNA damaging therapeutics.New set of quinoline -based small molecules were designed and synthesized. Three molecules showed good cytotoxicity against HCT116.SAR studies indicate the importance of the substituent being electron donating in nature and the position to be para in order to obtain maximum effect against cancer cells. Docking studies provide additional support to the already observed ATM inhibition through Western-Blot analysis [3]. The next review deals with the analysis of molecular mechanisms of a rare genetic disease tuberous sclerosis complex (TSC), which is characterized by non-cancerous tumors in multi-organ systems in the body. An extensive review on structural information of TSC1 and TSC2, homology modelling of human TSC1, functional role of TSCc in protein-protein interaction, TSC in mTOR pathway, disruptive mutations in TSC, current TSC treatment are presented. The biochemical, genetic, structural biology, and clinical aspects of the tuberous sclerosis complex disease are discussed as well as drug discovery problems for its cure.The main conclusion is that despite significant progress in TSC research,the critical challenge in the treatment of TSC is to meet with the efficacy of a drug in both CNS as well as tumor growth in various parts of the body. Another interesting therapeutic target is the TSC1-TSC2 complex itself [4]. The next paper refers to the Acetyl-Cholinesterase (AChE), which is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine being the target of most of the clinically used drugs for the treatment of AD.The paper focused on the development of acetyl-(AChE) and butyrylcholinesterase (BuChE) inhibitors belonging to viable strategies for treatment of dementia and other diseases related to decrease in cholinergic neurotransmission. Several novel N,N-disubstituted carbamates, thiocarbamates, N-n-alkyl monosubstituted carbamates and compounds with modified salicylanilide core (positional isomers, Schiff base instead of amide) were synthesized and evaluated as potential inhibitors of acetyl-and butyrylcholinesterase. A wide range of the derivatives showed an enhanced activity when compared to the parent salicylanilide 1 and also lower IC50 than the carbamate drug rivastigmine [5]. The next paper also deals with AChE and BuCheE inhibitors. Based on the knowledge that hydrazide-hydrazones scaffold have been known with various biological activities including inhibition of acetyl-(AChE) and butyrylcholinesterase (BuChE) several iodinated hydrazide-hydrazones and their analogues were synthesized and evaluated for their ability to inhibit acetyland butyrylcholinesterase in vitro. The influence of 4-substitution of the hydrazide part as well as position of hydroxyl group at hydrazone moiety was investigated. The molecular modelling study was performed in order to rationalize in vitro inhibition results and structure-activity relationships and to estimate possible binding modes of the most active prepared molecules with both enzymes. Many compounds shared lower IC50 values for AChE and some of them are also comparable against BuChE in comparison with rivastigmine. Nevertheless, they were less potent than tacrine and doneperezil [6].

Great efforts have been done to understand the progression of complex cancer diseases. Further, research is being done in the development of cancer therapeutics as to drug delivery and this still is continuing. Cancer therapeutic research involves the development and studies of various molecules including traditional cytotoxic drugs, specific kinase inhibitor and also monoclonal antibodies. This issue focuses on liver, colon, and prostate cancers along with drug delivery mechanism. The most common type of liver cancers are hepatocellular carcinoma (HCC) that initiate from hepatocytes of the liver while other less common liver cancers are intrahepatic cholangiocarcinoma and hepatoblastoma. HCC can happen due to mutations in DNA, chronic hepatitis infection and sometimes are due to unknown reasons. Prostate cancer occurs in the prostate gland of men and can spread or metastasize to different parts of the body. Most prostate cancer is adenocarcinomas that develop from gland cells. Further, some rare cancers that develop in prostate glands are transitional cell carcinoma, small cell carcinoma, sarcomas, and neuroendocrine tumors. Notably, colon cancer initiates in the large intestine of the digestive tract. Initially, noncancerous polyps appear in the large intestine and gradually a few polyps becomes malignant. This can happen at any age but mostly occurs in elderly people. Interestingly, essential oils from the bark of Cedrus deodara have shown anticancer efficacy against colon cancer. These essential oils contains several compounds including 2-(tert-butyl)-6-methyl-3-(2-(trifluoromethyl)benzyl)imidazo[1,2a]pyridine, 9- octadecenoic acid, copaene, longifolene, and 9(E), 11(E)-conjugated linoleic acid that inhibit cancer cell proliferation, inducing apoptosis, and impair NFкB signaling. Several plant-based anti-cancer medicines have poor bioavailability. Nanotechnology has the potential to overcome the bioavailability problem of phytomedicines. Notably, nanoparticles play an important role in the delivery and improvement of efficacy of plantbased medicines in cancers including hepatocellular carcinoma. Nanocarriers improve the pharmacokinetics of nanophytomedicines including liposomes, micelles, dendrimers, carbon nanotubes and nanosponges. There are several phytomedicines conjugated with nanoparticles that are discussed including curcumin, querectin, berberine, resveratrol and triptolide. Molecular imprinted polymers (MIPs) can be used for sustained release of drugs in cancer therapeutics as a novel drug delivery mechanism. Several studies of anticancer agents with MIPs have been discussed including rivastigmine, doxorubicin, paclitaxel, quercetin, chitosan and R-thalidomide. MIPs can help in improvement of drug delivery efficiencies of anti-cancer agent. The proteogenomics approach is one of the emerging techniques that include amalgamation of proteomics, genomics and transcriptomics to understand the progression of various complex diseases including cancer. It provides in-depth knowledge of diseases by finding biomarkers, targets and biological processes. The proteogenomics approach has observed repression of PTEN, mutations in TP53 and SPOP in both primary prostrate tumor and metastatic prostrate tumor, while several new mutations were observed in metastatic prostrate tumor. Further, proteogenomics can be used in personalized medicine.

This editorial provides a brief overview of the thematic issue and the papers in it. The thematic issue is proposed to help chemists and biologists track the most recent advances in drug discovery and cancer diagnoses. The process of drug discovery involves the identification and validation of biological targets, the identification and optimization of lead compounds, preclinical development, and clinical trials. Cancer is a major public health problem in the world. The results of tissue diagnosis, blood tests, computed tomography scans, and cytogenetic analyses can provide informative clues about molecular changes and indicate proper prognoses. Timely detection of cancer significantly improves cancer outcomes by providing care at the earliest possible stage thus contributing greatly to the prevention and exacerbation and has become an important public health strategy in all settings. The collection of this thematic issue includes five articles. The first one reviews the current advances and limitations of deep learning in anticancer drug sensitivity prediction. The next review summarizes the most recent and high-quality research related to anticancer activities of Vitamin C. The third one reports the efficacy of two different sets of natural products (terpenoids and flavonoids) towards caspase-3 activity. The fourth one proposes a novel in silico method for predicting cancer biomarkers in human body fluids. The fifth article performs an in silico and in vitro investigation on isothymusin, which serves as a potential inhibitor of cancer cell proliferation.

Tremendous efforts were made to treat cancer ranging from small molecules to monoclonal antibodies. According to World Health Organization, about 30 to 50 % of all cancer cases may be preventable. Unfortunately, 9.6 million people have died due to cancer globally in year 2018. Notably, one in 6 women and one in 5 men have chance to develop cancer during their lifetime. This issue discusses about testicular, gynecological and liver cancer along with cancer therapeutics. Testicular cancer mostly initiate in germ cell of testicle. Majority of the cases were reported in adult men and were treatable in early stages of cancer using surgery, radiation and chemotherapy. Population pharmacogenetics, clinical trial, genetic determinants of chemotherapy induced toxicity and signaling pathways in testicular cancer have been discussed. Signaling pathway and application of natural products such as campothecin, paclitaxel, podophyllotoxin, and vincristine have been discussed in gynecological cancers including ovarian, cervical and uterine cancer. Unfortunately, majority of the gynecological cancer get diagnosed at late or advance metastatic stage. Flavonoids have potential to treat cancer and also play important role in overcoming the drug resistance mechanism such as in case of Fisetin, and Quercetin. It can be used in combination with other cancer drugs as synergistic therapy. Bioavailability of flavonoids can be enhanced by several methods including derivatization, micro and nano delivery system that may help to enhance the pharmacokinetic and pharmacodynamics properties of flavonoids. Nanomedicine has great application in therapeutics of hepatocellular carcinoma (HCC) and has potential to play important role in cancer imaging and diagnostics. Nanotechnology drug delivery system successfully delivers the drug at specific target site by crossing the physiological barriers. Lipid-based nanoparticles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, carbon nanotubes, metallic nanoparticles, dendrimers and its applications have been discussed in details. Superparamagnetic and paramagnetic nanoparticles help in imaging of cancer by enhancing the reliability and sensitivity of tumor diagnosis and several nano formulations are under clinical trial for liver cancer. Monoclonal antibodies have been found to be very useful in cancer therapeutics. Trastuzumab is one of the admired molecular antibodies that help to control breast cancer in HER2 positive patients. In addition, Cetuximab is well-known epidermal growth factor receptor (EGFR) inhibitor for treatment of non-small cell lung cancer, while Bevacizumab is an antiangiogenic agent that binds with vascular endothelial-derived growth factor (VEGF) and used as anticancer agent in several cancer including colorectal cancer. Efficient bioavailability and target specific binding are important factor for success of monoclonal antibodies as cancer therapeutics.

Drug discovery is one of the most complicated processes and establishment of a single drug may require multidisciplinary attempts to design efficient and commercially viable drugs. The main purpose of drug design is to identify a chemical compound or inhibitor that can bind to an active site of a specific cavity on a target protein. The traditional drug design methods involved various experimental based approaches including random screening of chemicals found in nature or can be synthesized directly in chemical laboratories. Except for the long cycle design and time, high cost is also the major issue of concern. Modernized computer-based algorithm including structure-based drug design has accelerated the drug design and discovery process adequately. Surprisingly from the past decade remarkable progress has been made concerned with all area of drug design and discovery. CADD (Computer Aided Drug Designing) based tools shorten the conventional cycle size and also generate chemically more stable and worthy compounds and hence reduce the drug discovery cost. This special edition of editorial comprises the combination of seven research and review articles set emphasis especially on the computational approaches along with the experimental approaches using a chemical synthesizing for the binding affinity in chemical biology and discovery as a salient used in de-novo drug designing. This set of articles exfoliates the role that systems biology and the evaluation of ligand affinity in drug design and discovery for the future.

Development of new and more selective drugs is a main objective in medicinal chemistry. In fact, most drugs interact with unintended, often unknown, biological targets and these off-target interactions may lead to clinical toxic events and less efficacy. In this contest, computational approaches may play a relevant role while looking for new and more selective drugs against a specific target. Several computational approaches have been developed in the recent years with proven efficacy. This special issue of the Current Topics in Medicinal Chemistry is aimed at illustrating new developments and recent findings in the field of computational approaches aimed at predicting new and selective drugs against specific targets. The first paper by Garcia-Hernandez et al., focuses on the use of optimization techniques in order to learn the edit costs used when comparing graphs by means of the graph edit distance. This distance might provide useful structure-activity information for future drug design efforts. Overall, this paper shows that the graph edit distance along with learned edit costs is useful to identify bioactivity similarities in a structurally diverse group of molecules [1]. The second paper by Concu et al., shows the application of an innovative machine learning approach to predict the selectivity of new drugs against a specific target, in this case one of the two isoforms of the monoamine oxidase [2]. The third paper has been developed by Kumar et al., and present A Multi-layered Variable Selection Strategy for QSAR Modeling of Butyrylcholinesterase Inhibitors. Variable selection is a relevant field in QSAR in order to develop robust and reliable models [3]. The fourth paper by Gómez-Ganau et al., presents an in silico and in vitro study of the development of new epidermal growth factor receptor inhibitors. This receptor is a major target in medicinal chemistry since its dysregulation is involved in several types of cancers, such as breast, lung, gastric, etc. [4]. The last paper developed by Pei et al., reports an interesting review on the relationships between HRV signals and the personalized drug response in different diseases and patients since there is still a great variability and the mechanisms are complex and remain unclear [5].

Kinases have proved to be valuable therapeutic targets as more than >50 kinase inhibitors have received regulatory approval for therapeutic use. The success of kinase inhibitors has spurred many kinase-targeted drug discovery projects across pharmaceutical industries and in academia during the last decade. Kinases are not only implicated in cancer biology, but also in several other diseases such as rheumatoid arthritis, Alzheimer’s disease, pulmonary fibrosis, and several more. The overall objective of this thematic issue was to gather together the role of various kinases in different diseases along with preclinical and clinical data of small molecule kinase inhibitors. Part I of the thematic issue [1] has covered the biology and small molecule inhibitors of tau kinases, phosphoinositide-3-kinases, EGFR, PKCβ, along with one review on natural products and plant extracts as kinase inhibitors. The present Part II of the thematic issue covers two important serine-threonine kinases viz. glycogen synthase kinase 3β(GSK-3β) and cyclin-dependent kinases (Cdks). Apart from this, the computational strategies involved in designing selective kinase inhibitors are also discussed in this issue. The GSK-3β isoform is one of the serine-threonine kinases that areimplicated in cancer, Alzheimer’s disease and inflammatory diseases. It has been extensively studied in Alzheimer’s disease because of its major role in hyperphosphorylation of tau protein. Jadhav and coworkers [2] have reviewed the role of GSK-3 in various diseases, along with its inhibitors which are in the preclinical and clinical stages. Another extensively studied serine threonine kinase is a group of CDKs for which three small molecule inhibitors have received FDA approval with many more at the clinical trial stage. The key success in this effort lies in achieving the right balance between the therapeutically effective dose and the maximum tolerated dose (MTD). Jain and coworkers [3] have reviewed the physiological roles of CDKs, followed by coverage of the preclinical and clinical pipeline and key dose-limiting toxicities (DLTs) observed in clinical trials. All kinases share a conserved ATP binding site, and thus the selective targeting of a particular kinase is always a challenging task. Historically, computational approaches have been largely employed to design selective kinase inhibitors. P.S. Kharkar [4] has discussed computational tools for the design of selective tyrosine kinase inhibitors. As Guest Editor for this thematic issue, I express my gratitude to all the authors, reviewers, the journal editors, and the publisher who have helped to bring out this issue.

Cancer is a serious health problem and the second leading cause of death around the whole world only behind cardiovascular diseases [1,2]. Unfortunately, the morbidity and mortality of cancer are projected to grow for a long period, and death from cancer was twice that from cardiovascular disease in the high-income countries according to the latest the Prospective Urban Rural Epidemiology (PURE) study [3]. The past decades have witnessed tremendous progress in cancer theranostics. Currently, approximately one-third of cancers can be prevented, one-third can be cured through early diagnosis, and the remaining one-third can be associated with prolonged life and improved quality of life if the appropriate treatment is provided [4]. This special issue of Current Topics in Medicinal Chemistry on “Development and advances of drugs for cancer theranostics” contains three review articles and three original research papers, covering broad aspects of anticancer research. Heterocycles are common fragments found in the vast majority of drugs and play a pivotal role in the development of novel anticancer agents. In this special issue, the reviews entitled “Recent development of 1,2,4-triazole-containing compounds as anticancer agents”, “Recent advances in β -lactam derivatives as potential anticancer agents” and “1,3,5-Triazine-azole hybrids and their anticancer activity” summarize recent advances of 1,2,4-triazole, β-lactam and s-triazine-azole derivatives as potential anticancer agents as novel candidates with high efficiency and low toxicity. Hybridization and dimerization represent two promising strategies to develop novel anticancer agents since hybrid molecules and dimers have the capacity to enhance anticancer activity, overcome drug resistance, and reduce side effects. The original research papers entitled “The anti-breast cancer potential of bis-isatin scaffolds”, “The in vitro anticancer activity and potential mechanism of action of 1-[(1R,2S)-2-fluorocyclopropyl]ciprofloxacin-(4-methyl/phenyl/benzyl-3-aryl)-1,2,4-triazole- 5(4H)-thione hybrids”, and “Moxifloxacin-isatin hybrids tethered by 1,2,3-triazole and their anticancer activities” describe the quinolone and/or isatin hybrids/dimers with promising anticancer activity. Some of them demonstrated promising potential activity against both drug-sensitive and drug-resistant cancer cells, and these quinolone and/or isatin hybrids/dimers may provide valuable therapeutic intervention in the cancer control. In recent years, great achievements have been made in the development of novel candidates for cancer theranostics, and some of them have already been approved for the cancer therapy. However, the complexity of cancer development and the continuous emergency of drug-resistant cancers make a long way to go for mankind to completely control and eradication of cancers. This issue is an endeavor to outline the advances in several heterocycles with anticancer potential developed in recent 20 years. The structure-activity relationships and mechanisms of action are discussed to provide an insight for rational designs of more effective candidates.

Mental health, which is an integral part of health and well-being, is defined as "Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity" by the World Health Organization (WHO) [1]. Psychiatric disorders, generally characterized by a combination of abnormal thoughts, emotions, behavior and relationships with others, include affective disorders as depression or bipolar affective disorder, schizophrenia and other psychoses, dementia and many others [2]. Globally, mental disorders affect a large part of the society at some point in their lives. According to WHO data, an estimated 264 million people are affected by unipolar depression; bipolar disorders and dementia have been reported to affect about 45 and 50 million people worldwide [2]. In recent years, growing evidence supports that inflammatory pathways are important in the pathophysiology of psychiatric disorders [3]. This is especially interesting as individuals suffering from psychiatric diseases frequently also suffer from other comorbid somatic disorders with known inflammatory background [4]. Otherwise psychosocial stress in general has been associated with increased levels of inflammatory biomarkers [5]. Furthermore, somatic comorbidities as e.g. adiposity or cardiovascular disease are increased in individuals with mental disorder leading to reduced life-expectancy and have also been associated with low grade inflammation [6]. Some evidence on this subject shows that nonsteroidal anti-inflammatory drugs (NSAIDs) might have effects on depressive symptoms. The study of Bauer IE A et al. (2018) suggests an adjunctive therapeutic benefit of Aspirin and N-Acetylcysteine in bipolar disorders by a reduction in depressive symptoms [7]. Furthermore, according to a meta-analysis that examined 36 randomized clinical trials, anti-inflammatory drugs were highlighted to improve antidepressant treatment effects compared to placebo [8]. In another study, TNF-α inhibitors suggested to slow down cognitive decline and improve daily activities in Alzheimer’s disease [9]. Besides clinical studies, in silico studies focused on the structural similarity of molecules acting either an anti-inflammatory or antidepressant activity are also remarkable, in recent years [10, 11]. The presence of similar molecule structure used in the treatment of depression and inflammation seem to be really promising for design of novel drugs. It is not yet known exactly how inflammation may be involved in the pathogenesis and the treatment of mental disorders and therefore, in the discovery of novel potent molecules for the treatment of psychiatric disorders comorbid with inflammatory diseases have only been explored partly and require further research efforts. In the previous issue focusing on the connection between inflammation and depression [12], four reviews were published to clarify common mechanisms between depression and inflammatory disease and current drugs with anti-inflammatory and antidepressant properties were also highlighted [10, 13- 15]. The thematic issue on “New approaches for the treatment of mental disorders comorbid with inflammatory diseases” of Current Topics in Medicinal Chemistry focused especially on molecular mechanism concerning the overlap in inflammatory pathways between mental disorders (including psychosocial stress) and comorbid somatic condition. This issue also explores which markers increase in both diseases, the importance of tryptophan-kynurenine pathway, the possible effects of immunomodulatory agents on mental illness for a better understanding of the underlying mechanisms of both diseases. The first article of the issue focused on kynurenine metabolism in bipolar affective disorders. Differences between euthymic, depressive and manic episodes in this pathway, as well as associations with the severity of current symptoms have been explored [16]. Furthermore, the review of Wadhawan A et al. suggests that chronic peridontitis perpetuates inflammation in individuals with neuropsychiatric disorders [17]. Especially polymicrobial infection with Porphyromonas gingivalis might play a central role and additionally induce somatic comorbidity as it negatively influences coronary and peripheral arteries. The second systematic review focusses on ketamine as a treatment option for individuals suffering from depression. Acute versus long-term treatment as well as evidence of the treatment in specific population is discussed and clinical aspects are highlighted [18]. Last, but not least, the article by Leblhuber F et al. reviews data on biomarkers with focus on tryptophan breakdown and immune activation markers in Alzheimers disease [19]. They suggest the existence of an outside brain contribution to Alzheimer’s disease that might be able to predict the severity of the cognitive impairment in patients. Although researches on the use of anti-inflammatory drugs in mental illnesses are increasing day by day, more studies are needed to understand to clarify the common molecular mechanisms in individuals with mental disorders comorbid with inflammatory disease. Especially changes in tryptophan breakdown as well as further different inflammatory pathways should be explored in clinical studies in real live settings. Also, in silico methods for investigations about the structural similarity of the drugs used for the treatment of depression and inflammation with may contribute to understand the underlying mechanism between depression and inflammation.

This special Issue on “Host Defence Peptides in medicinal chemistry: identification, engineering, characterization and beyond” has been edited with the purpose of providing current achievements and future perspectives in the exciting field of peptide-based medicinal chemistry. In particular, attention is focused on naturally occurring Host Defence Peptides (HDPs), a suggestive source of peptide-based therapeutic agents. Issue gives an overview of recent advances in the research area of antimicrobial peptides (AMPs), more properly named host defence peptides (HDPs) to better reflect their roles as immunomodulatory mediators and, under some circumstances, antimicrobial agents, actually considered as promising candidates for the development of new anti-infective agents. The World Health Organization (WHO) has recently raised serious concerns about the increasing worldwide spread of microbes resistant to the available antibiotics/antimycotics and the shortage of new and effective drugs in the pharmaceutical industry [1]. Indeed, while multidrug-resistant bacteria have rapidly spread in the past several decades, the discovery of novel classes of antibiotics has slowed down since 1987 due to reduced economic incentives and challenging regulatory requirements [2,3]. This makes antibiotic resistance one of the biggest threats to global health, food security, and development today. In this scenario, HDPs, a ubiquitous part of the innate immune defence in all classes of life, have been widely studied and show great potentialities as small molecule antibiotics effective even on bacterial biofilms [4-7]. Indeed, in contrast with traditional antibiotics which generally target intracellular enzymes whose mutations can mediate the development of resistance phenotype, most HDPs are endowed with multiple activities [8]. Since bacterial membrane is their main target, acquisition of resistance to HDPs would require a deep reorganization of membrane lipids composition, with a consequent significant harm to the same bacteria [9]. This feature associated to HDPs selectivity for bacterial/fungal cells and to their wide range of activities (e.g. chemotactic, wound healing, angiogenic, anti-endotoxin activities) make them very attractive templates for the generation of new antimicrobials with expanding properties [8,9]. More than 3,000 HDPs have been reported and characterized so far [10], and six of them have been approved by the U.S. Food and Drug Administration (FDA), i.e. gramicidin D (Neosporin® manufactured by Monarch Pharmaceuticals, Inc., Bristol, TN, USA), daptomycin (Cubicin® manufactured by Merck & Co., Inc., Kenilworth, NJ, USA), vancomycin (Vancocin®HCl manufactured by ANI Pharmaceuticals, Inc., Baudette, MN, USA), oritavancin (Orbactiv® manufactured by Melinta Therapeutics, Inc., New Haven, CT, USA), dalbavancin (DalvanceTM manufactured by Allergan Sales, LLC, Irvine, CA, USA), telavancin (Vibativ® manufactured by Theravance Biopharma, Inc., San Francisco, CA, USA) [11]. Indeed, despite the great therapeutic potentialities of HDPs, their use as drugs has been limited so far by several factors, such as: (i) high production costs, (ii) low stability and bioavailability in vivo, (iii) the potential to induce an immunogenic response, (iv) toxic effects, and (v) binding to serum proteins with consequent peptide inactivation. However, several experimental strategies have been adopted to overcome the disadvantages related to the development of peptide molecules as new therapeutics, and HDPs continue to attract the interest of biopharma companies due to their unique ability to act in synergism with conventional antibiotics, their relatively small size, the capability to neutralize endotoxins, their low minimum inhibitory concentration (MIC) values, their effectiveness against bacterial biofilms, their antiviral properties, and their anticancer activity against multidrug resistant (MDR) cancer cells. The goal of the present Issue is to provide a comprehensive overview of the pharmacological potentialities of HDPs, with a special focus on naturally occurring HDPs. It has been reported that several eukaryotic proteins, with functions not necessarily related to host defence, act as a source of cryptic antimicrobial peptides endowed with several biological activities of potential pharmacological interest [12-15]. Based on this observation, human proteome could be fascinatingly seen as a yet unexplored source of bioactive molecules with great therapeutic potential. To cite Albert Einstein: “Imagination is more important than knowledge. Knowledge is limited. Imagination encircles the world”. Indeed, recently discovered “cryptides”, derived from many well-studied proteins, have been found to be involved in the regulation of a wide range of cellular processes including neuronal signalling, inflammatory response, adaptive immune response, differentiation, cell proliferation, wound healing and angiogenesis [8,9]. In the present Issue, the review by Li and co-workers focuses on the ability of HDPs to act in synergism with conventional antibiotics. It is emphasized how synergistic effects open the way to the development of successful combinatorial therapeutic approaches, in which effective doses of conventional antibiotics are significantly lowered, with the possibility to manage the serious global health threat of antimicrobial resistance. Being HDPs able to work as adjuvants at non-toxic concentrations also in animal models, they are presented as ideal safe agents to develop novel effective combinatorial therapies. The review by Casciaro and co-workers also focuses on the ability of HDPs to synergize with different antibiotic classes or different natural compounds. In particular, authors focus on the effects that HDPs cause at concentrations below the minimum growth inhibitory concentration (MIC) value and on the underlying molecular mechanisms. The effects that sub-MIC levels of HDPs can have on bacterial pathogenicity are clearly summarized by showing how signalling pathways can be valid therapeutic targets to threat infectious diseases, thus supporting the high potentiality of HDPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities. In an attempt to highlight the great potentiality of human proteome as a yet unexplored source of bioactive host defence peptides (HDPs) endowed with multiple activities of pharmacological interest, reviews by de Oliveira Costa and Franco, Bosso and co-workers, Gaglione and co-workers, and by Boutin and Dalpke are focused on “cryptic” HDPs. In particular, review by Oliveira Costa and Franco is focused on the development of optimized sequences based on natural cryptic HDPs by also presenting clinical-phase studies of cryptic HDPs (natural or optimized), thus pointing out the great potentiality of these molecules to be applied in medicinal chemistry. Bosso and co-workers focus on enzymes as a precious source of novel cryptic HDPs, thus consolidating the fascinating hypothesis that proteins have a second or even multiple biological missions in the form of one or more bioactive peptides. In particular, the review by Bosso and co-workers focuses on a panel of HDPs, identified in all canonical classes of enzymes, and provides a detailed description of hydrolases and their corresponding HDPs, showing that this structurally sophisticated class of enzymes is characterized by a high content in cationic and amphipathic cryptic bioactive peptides. Review by Gaglione and co-workers also focuses on cryptic HDPs released, in specific circumstances, by several eukaryotic proteins with defined physiological roles upon protein cleavage by host and/or bacterial proteases. In particular, authors focus on promising bioactive peptides identified into human apolipoproteins E, B, and A-I sequences. Several human apolipoproteins derived peptides are described and reported to be endowed with antibacterial, anti-biofilm, antiviral, antiinflammatory, anti-atherogenic, antioxidant, or anticancer activities in in vitro assays and, in some cases, also in in vivo experiments on animal models, thus opening interesting perspectives to the applicability of Apo-derived HDPs in biomedical field. Review by Boutin and Dalpke focuses on the ability of eukaryotes or microorganisms to produce antimicrobial compounds playing key functional roles. Since most of producing organisms are uncultivable by using classical methods, the use of extended culture or DNA based methods (metagenomics) to discover novel compounds is clearly described. An overview of the environmental sources to discover new natural compounds from microbiome is presented together with the description of culture- based and culture independent (metagenomic) approaches developed to identify novel antimicrobials. Finally, in an attempt to explore practical applications of HDPs, the review from Kurbasic and co-workers reports on the applicability of self-assembling HDPs in the design and production of supramolecular antimicrobial hydrogels based on peptides. These soft materials are described as promising agents to threat infections, also considering that stimuli-responsive systems could be assembled/disassembled ad hoc with the consequent opportunity to switch on/off their bioactivity as needed. Developments in this emerging area are extensively described, thus highlighting the great potentiality of the next generation of supramolecular antimicrobial peptides as innovative therapeutic materials. I really hope that this special Issue will increase the interest in host defence peptides by providing a fascinating picture of the huge potentialities of synthetic and naturally occurring HDPs as novel promising therapeutics. Indeed, reported evidence clearly indicate that the future of HDPs is still bright and that they represent a precious starting point to develop a new generation of drugs and therapeutic approaches in the near future. I’m greatly thankful to all the authors and the reviewers and express my sincere appreciation for their valuable contributions to this Issue. I’m also very grateful to the Associate Editor Dr. Ambreen Irshad Sheikh and to the Assistant Manager Mr. Yasir M. Maqsood for giving me the opportunity to organize and edit such an interesting Issue and for their continuous support and assistance throughout the production process in a peculiar time of my life characterized by the birth, in the last November, of my second daughter Beatrice.

Neurodegenerative Diseases (NDs) are age-dependent disorders. They include Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS). These neurodegenerative diseases impair memory, cognition and movement, but currently none of them is curable, and the treatments available only manage the symptoms or halt the progression of the disease. It is suspected that these NDs may overtake cancer to become the second-most prevalent cause of death after cardiovascular diseases. Therefore, attempts have been made to find drugs against them. This thematic issue has attempted to present the advancement in this direction providing the guidelines for further research on this burning problem. The present issue contains five excellent articles written by experts. The very first article entitled “Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders” written by Chandra et al. discusses that the gut-brain axis (GBA) plays a major role in the pathogenesis of many neurodegenerative disorders [1]. Authors have tried to explain as to how GBA leads to such diseases and how it can be exploited to find drugs to treat NDs. The second article written by Datta et al. on “Advances in Studies on Stroke-Induced Secondary Neurodegeneration (SND) and Its Treatment” talks on secondary neurodegeneration (SND) exclusively observed after the first incidence of stroke. SND can lead to cognitive and motor function impairment, finally causing dementia [2]. The article reviews the available reports on SND pathophysiology, detection techniques and possible treatment modalities that have been attempted to date. In article third entitled “Role of Flavonoids in Neurodegenerative Diseases: Limitations and Future Perspectives”, Maan et al. have discussed the role of flavonoids in neurodegenerative diseases [3]. Flavonoids, a group of natural dietary polyphenols, are known for their beneficial effects on human health and by virtue of their various pharmacological effects, like anti-oxidative, anti-inflammatory, anti-carcinogenic and neuroprotective effects, they have now become an important component of herbal supplements, pharmaceutics, medicines and cosmetics. Alzheimer's disease (AD), one of the NDs, has a detrimental effect on the brain nerve cells, resulting in the dysfunctioning of neurological areas involved in processing of information in the brain. The causative agents of this disease are some enzymes and proteins, such as β-secretase, also known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), γ-secretase, and tau protein. Therefore, in article fourth entitled “Recent Studies on Design and Development of Drugs against Alzheimer’s Disease (AD) Based on Inhibition of BACE-1 and Other AD-causative Agents”, Gupta and Patil have presented the structural aspects of these enzymes and their importance in the design of potent anti-AD drugs [4]. However, though several potent drugs against AD have been developed based on these causative agents, vaccines are thought to be more likely to prevent AD instead of providing treatment by drugs. Therefore, Kabir et al. have focused in the last entitled “Emerging Promise of Immunotherapy for Alzheimer’s Disease: A New Hope for the Development of Alzheimer’s Vaccine” on the recent progress that has been made to achieve an effective AD vaccine [5]. I have greatly enjoyed reading all these articles and hope so will do the readers and find them useful for further advancement in research on neurodegenerative diseases.

The phosphorylation of proteins is one of the key post-translational events essential to activate or deactivate various enzymes and receptors in the cellular machinery. This event is regulated by two set of enzymes namely kinases and phosphatases. The kinases have been implicated in regulation of the signal transduction mechanisms and thus their over- or underexpression occurs in several diseases including many cancers, some of the neurodegenerative diseases and also in some autoimmune diseases. The event of phosphorylation occurs primarily at three amino acid residues namely serine, threonine and tyrosine; and thus based on this, kinases are broadly categorized into serine/threonine kinases and tyrosine kinases [1]. Apart from protein kinases, there exist another important class of kinases which is lipid kinases [2]. The examples of serine threonine kinases include protein kinase A-C, cyclindependent kinases, glycogen synthase kinase-3 α/β, check-point kinase, mitogen activated protein kinase, polo-like kinase, calmodulin dependent protein kinase III, BAF kinase, etc. The examples of tyrosine kinases include Erb-B family (includes EGFR), vascular endothelial growth factor receptor (VEGFR) family, SRC tyrosine kinase, v-Abl tyrosine kinase, dual specificity protein kinase (Dyrk-1A and CLK-1), Janus kinase (JAK), etc. The lipid kinases mainly include phosphoinositide-3-kinase (PI3K) and sphingosine kinase (SphK). It is interesting to mention that 20-33% of drug discovery efforts worldwide involve the kinases as targets. Over the period of last two decades, kinases have immerged as most valuable therapeutic targets, primarily in the oncology domain. After the seminal discovery of protein kinases as potential therapeutic targets for cancer in 1994 [3, 4], the last two decades have witnessed a great success for kinase inhibitors in the clinic. This has resulted in approval of more than 50 kinase inhibitors for therapeutic use (Source: US-FDA website). Imatinib is the first FDA approved kinase inhibitor (approved in 2001) for treatment of CML. The majority of kinase inhibitor approvals are in the area of oncology; however few inhibitors have also been approved for other indications such as rheumatoid arthritis, idiopathic pulmonary fibrosis, myelofibrosis, and also for the management of thrombocytopenia. The clinical and preclinical pipeline in this domain is also very rich in number. The objective of this thematic issue is to critically review the role of various kinases in the pathology of various diseases, and most importantly the drug discovery paradigms such as computational approaches, medicinal chemistry research, preclinical studies and clinical trials on small molecule kinase inhibitors. The current issue (part I of the thematic issue) includes five articles, covering kinases involved in tau hyperphosphorylation, phosphoinositide-3- kinases, EGFR, the tyrosine kinase; and protein kinase C-α. Authors and coauthors from different parts of the world (5 countries) contributed to this issue to make it an unique collection. Tau hyperphosphorylation is one of the key pathological events in Alzheimer disease, leading to the formation of neurofibrillary tangles, which gets deposited inside neurons. Kinases are the enzymes which catalyze the process of tau hyperphosphorylation. Hassan and workers [5] have provided an overview on various kinases which are involved in hyperphosphorylation of tau protein. The implications of these kinases in Alzheimer disease pathology along with small molecule modulators have been discussed. Phosphoinositide-3- kinases have attracted wide attention among medicinal chemists because of their involvement in cancer progression. The isoform selectivity appears to be very important aspect particularly in this class of kinases. Each PI3K isoform has different role in a particular disease. For example, the α-isoform gets overexpressed in cancers, and thus this isoform plays crucial role in the pathogenesis of cancers, in comparison to other isoforms. R.R.Y. Bheemanaboina [6] has reviewed various aspects of PI3K isoform-selectivity and their role in different diseases along with small molecule inhibitors. The author has provided a comprehensive compilation of all isoform-selective PI3K inhibitors. Natural products have contributed significantly in oncology domain in comparison to other therapeutic areas. More than 70% of drugs contain NP scaffold. Similarly, there are numerous reports on kinase inhibitory activities of plant extracts and pure natural products. Ahemad and coworkers [7] have revieved the kinase inhibitory activities of plant extracts and their secondary metabolites. Among the FDA approved kinase inhibitors >80% drugs are tyrosine kinase inhibitors, and many of them are EGFR inhibitors. Kumar et al [8] have reviewed the role of EGFR and its trafficking regulation by acetylation, and its implication in development of chemo-resistance. The review also highlights the need for dual targeting of EGFR and HDAC to tackle the resistance. Besides plant based natural products, the marine derived natural products (MNPs) have also significantly contributed in discovery of kinase inhibitors [9]. Amongst various MNPs investigated, bryostatin-1 is one of the classes of complex macrocyclic compounds, which were studied extensively despite of its structural complexity. Raghuvanshi and Bharate [10] have reviewed the preclinical and clinical information on this class of MNP. The present thematic issue focused on kinases, has gathered preclinical and clinical literature on important group of kinases at one place, and thus it will be useful to the researchers working in the various facets of drug discovery and also to the clinicians. In the capacity of a guest editor, I would like to express my gratitude to authors as well as reviewers who contributed to this thematic issue. I also express my appreciation to Journal's senior editor, Ambreen Irshad and Bentham Science Publisher for putting their quality time and valuable suggestions in organizing this special issue.

Bioengineered polymers and metal composites are becoming increasingly important both alone or in combination, for the development of endless conceivable biomedical applications such as drug delivery systems, regenerative medicine, theranostics, etc. [1-4]. Although metals/metal oxide nanoparticles show promise for diverse applications, there are many challenges faced in terms of their potentially toxic effects, which can be mitigated by efficient design and development of nano or microstructures, and effective delivery of metal/metal oxides NPs. In our previous work, we enhanced the biocompatibility of metal oxide (ZnO NPs) by designing the nanocomposites using polymers, which render them less toxic and increase the efficacy at lower doses [5-9]. This encouraged us to write a special issue of Current Topics in Medicinal Chemistry with the theme “Biological functions of polymers and metal composites” to provide an up-to-date literature for readers. Understanding the nanobiointeractions, correlations of physicochemical properties of nanomaterials with biological systems, and their kinetics are of significant interest in elucidating the fundamental relationship of NPs with biological systems. This special issue comprises reviews, original research article, and a perspective, covering the review of up-to-date advances on nanomedicinal approaches in viral zoonoses, inflammatory bowel disease (IBD), development of novel biosensors, delivery system, and the effect of the structural chemistry of polymers and metal composites on the biological applications, polymer metal nanocomplexes based delivery system, surface chemistry and toxicological issues. The authors/coauthors from different countries (India, Iran and Australia) contributed to this issue to make it unique. The opening article “Insight into Nanomedicinal Approaches to Combat Viral Zoonoses” provides significant introspection towards the multi-arrayed applications of nanomedicine to combat several important zoonotic viral diseases. It outlines the applications of nanomaterials in anti-viral vaccines or vaccine/drug delivery systems, diagnostics and therapeutic agents in combating the important zoonotic viral diseases in the recent scenario along with their potential benefits, challenges and prospects to design successful control strategies. The second article by Rani and colleagues entitled “Bioengineered Polymer/Composites as Advanced Biological Detection of Sorbitol: An Application in Healthcare Sector” describes the nanomaterials for the construction of ultrasensitive biosensors for the detection of sorbitol. It also elaborates biosensors with optical, electrochemical, piezoelectric, approaches for sorbitol detection and the importance of its discovery in healthcare. Prasad and colleagues in their article entitled “Application of Polymeric Nano-Materials in Management of Inflammatory Bowel Disease” reviewed the nanoparticles adequately, particularly metal and metal oxide NPs producing synergistic effects along with conventional drugs, which is beneficial for the therapeutic management of IBD. It includes prevalence, pathology, gut microenvironment and challenges for oral drug delivery, currently available therapeutic regimens, nano-interventions particularly metal and polymeric NPs in management, nano-interventions in the diagnosis of IBD including toxicological and regulatory issues. In the article “Polymer Metal Nanocomplexes Based Delivery System: A Boon for Agriculture”, Kaur and colleagues revealed that the metal and polymer-metal nanocomplexes are precision building blocks that can be used as protecting agents against phytopathogens by developing multifunctional delivery systems for various kinds of agrochemicals in soil or plants. Precise strategies that allow a fine degree of control over polymer microstructure and architecture are described in the article. Ongoing advancements in the field of sustained release of agri-inputs indicate that polymer-metal nanocomplexes have a great potential in agriculture as a delivery system to eradicate the diseases. Organic polymers and metal nano-particles are also used for nano-composite based sensor fabrication. The nano-composite increases the flow of electron between the electrode and analyte which helps in increasing the efficiency of the sensor for rapid detection of the analyte. Minakshi and Pundir and their colleagues reviewed the role of various metallic NPs, conducting polymers in the article entitled “Organic Polymer and Metal Nano-particle Based Composites for Improvement of the Analytical Performance of Electrochemical Biosensors”. To combat the problem of antibacterial resistance, Negahdary and his colleagues suggested an approach to use metal nanoparticles and have shown the antibacterial activity of zinc sulfide nanoparticles against bacteria Streptococcus pyogenes and Acinetobacter baumannii. Recent advances in Artificial Intelligence, propelled by deep learning, have been transformative across many important domains. Manuja and coauthor vision a fascinating outcome for the design and synthesis of polymeric nanocomposites and prediction of their behavior in biological systems from the available abundant data using novel approaches of Artificial Intelligence and Machine learning in their perspective “Artificial intelligence-based design of polymers and metal composites: a perspective”. This special issue will be useful for researchers working in the area of medicinal chemistry, bioengineering, nanotechnology and nanomedicine for humans and animals. This issue is unique and innovative and adds to the existing literature with current advancements.

The past decades have witnessed tremendous progresses in drug discovery. After a lackluster period of low number of new drug approvals by the U.S. Food and Drug Administration (US FDA) during the first decade of this century, there has been a steady increase of new drug approvals since 2010, with the peak of 2018 having 42 New Molecular Entities (NME) and 17 Biologics drugs being approved. Among 42 NMEs, 16 were anticancer drugs to treat acute lymphoblastic leukemia (ALL), refractory acute myeloid leukemia (AML), metastatic non-small cell lung cancer (NSCLC), metastatic breast cancer, metastatic melanoma, non-Hodgkin lymphoma and so on [1, 2]. This special issue of CTMC on “Structure-Based Design on Anticancer Drug Discovery” contains five review articles and one original research paper, covering broad aspects of anticancer drug research, including reviews of up-to-date advances to research targets of interest such as the epidermal growth factor receptor (EGFR), AKT and new drug targets being identified. In the opening contribution of this issue, Sabbah and her colleagues [3] present a very comprehensive review on EGFR, not only on monoclonal antibodies (mAbs) targeting EGFR, but also tyrosine kinase inhibitors that inhibit EGFR. This paper discusses drugs targeting different subtypes as well as T790M mutants of EGFR. More importantly, this paper details proteinprotein interactions in the EGFR pathway. The reactome pathways listed in this paper surely enriches the EGFR research field. This paper truly summarizes the major advances in the EGFR since our last paper, which was also published in this journal in 2011 [4]. The phosphatidylinositol 3-kinase–Akt cell signaling pathway has been under extensive investigation. In March 2019, the US FDA approved Piqray (alpelisib) as the first PI3K inhibitor to treat human epidermal growth factor receptor 2 (HER2)- negative, PIK3CA-mutated, advanced or metastatic breast cancer [1]. In addition, PI3K inhibitors Zydelig (idelalisib) was approved by US FDA in 2014 for lymphoma, and in 2017 another PI3K inhibitor Aliqopa (copanlisib) was approved to treat relapsed follicular lymphoma (FL). Thus, the PI3K/AKT pathway has shown clinical verification. Bowen and coworkers [5] discussed in detail the PI3K/AKT pathway and the downstream effectors, their phosphorylation sites and regulatory functions. In particular, this paper reviews the anticancer activity of the solenopsin A and its derivatives. It also covers recent AKT inhibitors that are under development. This surely is a very up-to-date advance in the field of the PI3K/AKT pathway and it enriches the PI3K anticancer studies since we published two review papers in 2013 and 2016, respectively [6, 7]. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have played a critical role in genetic programming and gene regulation during development and cancer. lncRNAs are frequently mis-regulated in cancers, and have been considered as novel biomarkers and pharmaceutical targets for lung cancer. In silico analysis for prediction of lncRNAs-miRNA interactions combined with experimentation shows that miR-509-3-5p inhibits cell proliferation and migration of lung cancer cells. The research by Li et al. has identified new target for lung cancer research [8]. Prostate cancer is a serious health concern with 1.2 million new cases of prostate cancer occurring in the U.S.A. in 2018 alone. Bartzatt reviews the risk factors, screening, and methods of detection of prostate cancer. This paper mainly summarizes the current standard treatments for prostate cancer and the dilemma of testosterone replacement therapy for such a disease [9]. Structure-based drug design relies not only on single proteins, but more so on the understanding of protein-protein interactions (PPIs). However, traditionally it is very challenging to design inhibitors targeting protein-protein interactions due to the flat and large nature of the surface. Kontoyianni and her colleagues [10] provide a state-of-the-art of protein-protein interactions, decoding the complexity, docking methods to study such interactions, paying particular attention to the drugability of PPIs and binding site identification with some very impressive examples, such as CXCR3 which has a critical role regulating angiogenesis, an important feature for cancer cell growth. Last but not least, Bowen and coworkers [11] discuss the very important topic of DNA methylation, which is critical in cell differentiation and expression of genes. Clinically, DNA methylation has been found in cancer [12], diabetes mellitus (DM) [13], and asthma [14]. This manuscript particularly reviews the computational software on modeling DNA structures, and discusses the important topics of the electronic effects on DNA structures. Anticancer drug discovery has achieved amazing milestones in the past decades and more and more drugs have been approved by the US FDA for anticancer treatment. It is an era filled with exciting news and astonishing progress. However, due to the complexity of cancer development, there is still a long way to go for mankind to cure all cancers. It is our hope that this issue will stimulate discussions and share perspectives to push forward the frontier in anticancer drug discovery.

This series of the journal Current Topics in Medicinal Chemistry (CTMC) was launched in 2011 by Prof. Gonzalez-Diaz H. (CTMC Enabling Tech Editor, Co-EIC, Europe Editor) with overall supervision of EIC, Dr. Allen Reitz. Since, the series has published >20 special issues guest edited by top tier professors/ researchers worldwide. In contraposition, and as complement, to classic CTMC issues, the issues of the present series combine in a single pot both experimental and computational areas of research. Main focus is on enabling technologies supporting the Drug Discovery process, such as: Computational Chemistry, Bioinformatics, OMICS, Combinatorial Chemistry, Data Analysis, etc. as well as experimental techniques (LC-MS/MS, FTIR, or NMR, etc.) combined or not with computational methods like Molecular Docking and Machine Learning (ML). Recently, we renamed the series as “New Experimental and Computational Tools for Drug Discovery”. The renamed series has published a total of seven special issues until this moment (1-7). The series also has an editorial co-laboratory project page [CTMC Drug Disocv. Series] (when visiting the web, a click shows details, project log, and other info). In the present issue we present the following works: The objective of the work of Seck et al. is to access 1,3-disubstituted-1,2,3-triazenes, a class of molecules with a high therapeutic potential [1]. As a result, it is obtained that all strains were sensitive, giving higher priority to the best MIC, 0.28 μM for 4c against Escherichia coli ATCC 25921. Also, compound 9, 3-isopropyltriazene was active in the five strains evaluated with very good 0.32 μM MIC against Escherichia coli and Pseudomonas aeruginosa and 0.64 μM against Enterococcus faecalis and Pseudomonas aeruginosa. The structure activity relationship was compared, concluding that electron extraction groups appear to increase antimicrobial activity [1]. The phototoxic and hemolytic activity of the organophosphate was determined by García-Soria et al. [2]. Alternative in vitro assays with human erythrocytes were used to predict the contaminating effect of these products on health. The percentage of organophosphorus hemolysis induced by photo-hemolysis formulated with surfactants in a concentration of 2 x 109 erythrocytes was evaluated. In this study the HC50 in red blood cells were similar for each organophosphate (Malathion and Methamidophos) indicating a very irritating action with a ratio classification (L / D) of 0.041 and 0.053, respectively. On the other hand, chlorpyrifos was classified as irritant with L / D = 0.14. The HC50 obtained in the photo hemolysis assays of irradiated red blood cells was similar for each organophosphate, indicating that there is no phototoxic action [2]. The present study by Khan et al. addresses the inhibition of α-glucosidase from various derivatives of kaempferol 1-3 [3]. In silico studies and in vitro assay were performed. The results showed a marked inhibition based on the enzyme concentration and the IC50 values were 137 ± 9.01, 110 ± 7.33, and 136 ± 1.10 mM for kaempferol 1-3 respectively much better than the standard, acarbose (290 ± 0.54 mM) [3]. A study was conducted on the experimental measurement of waste generation in the chemistry laboratories of the Department of Organic Chemistry II (UPV/EHU) by Montes-Bageneta et al. [4]. Two sources of data were generated. The first is the waste generated in the laboratories. The second is the anthropogenic and social factors related to the generation of waste obtained through a questionnaire. Finally, two PTML machine learning models were obtained that include chemical, operational and academic factors from 6050 cases of laboratory practices versus reference practices. These models predict the values of acetone residues with R2 = 0.88 and non-halogenated residues with R2 = 0.91 [4].

Synthetic or natural bioactive molecules are the essential scaffolds for the development of therapeutics. This special issue is the second part of the thematic issue “Bioactive Chemical Entities: Pre-clinical and Clinical Aspects”. This current issue includes three articles. The first article is entitled “Natural Products as a paradigm for the treatment of Coxsackievirus-induced Myocarditis” is by a group led by Prof. Madhu Khanna from Vallabhbhai Patel Chest Institute, University of Delhi, India. This article covers various topics viz. antiCVB3 and protease inhibitors, the impact of natural products on virus CVB3 and its associated viral proteases and strategies for efficient highthroughput screening [1]. The next article is “Quinoline Containing Sidechain Antimalarial Analogs: Recent advances and Therapeutic Application” was written by Mukesh C. Joshi and Timothy J. Egan. This is a comprehensive compilation of quinoline containing side chain antimalarial analogues along with their synthesis and therapeutic applications [2]. The third article on phytochemical quantitation reveals a sex, ploidy and ecogeography specificity in the expression levels of selected secondary metabolites in medicinal Tinospora cordifolia presented by Dr. Vijay Rani Rajpal and co-authors. This research article shows the first observations of ploidy specificity along with subtle sex and ecogeography influences on the expression levels of the secondary metabolome in T. cordifolia [3]. The editors are grateful to the publisher, and reviewers for their insightful suggestions and valuable support.

This thematic issue focuses on original reports and/or critical reviews of potential biological signatures of major neurological and psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorders, anxiety disorders, multiple sclerosis etc. The fundamental aim of the thematic issue is to bring forward the trans-diagnostic role of molecular, immune-inflammatory, and neuroimaging methods and data, which explains the broad spectrum of diagnostic and classification entities, by means of cross-validation of clinical and biological markers. This is achieved by advanced statistical methodology, including machine learning techniques. The underpinning mechanisms of disease are identified on three vertical levels of determination: [1] Neurochemical, exploring the molecular biomarkers of disease, such as microRNAs, pro-inflammatory mechanisms, neuro-oxidative and neuronitrosative stress in peripheral blood samples to be cross-validated against central biomarkers, e.g. magnetic-resonance spectroscopy [2]. Neuro-biological and neuro-anatomical signatures, outlined by structural magneticresonance imaging (quantitative MRI; voxel-based morphometry, in vivo histology of the central nervous system), and functional MRI, to detect the corresponding blood-oxygenation-level-dependent signal [3]. Clinical phenomenology datasets: scores from clinical interviews; cognitive and self-evaluation tests. The rationale of this collection is to delineate both vertical and horizontal sections of neurological and psychiatric diagnoses from the view of fundamental neuroscience. Biological signatures of disease are in fact a critical multi-dimensional approach to establish diagnostic validity in disciplines like neurology and psychiatry. Validity is described as convergent and divergent (or discriminative). When two different assessment tools for depression happen to coincide in their score/ interpretation, it is regarded as convergent validity and whenever their results are discrepant it is considered as divergent or discriminative validity. Divergent validity should generally characterize phenomena which differ each from other and in this respect is supposed to assist differential diagnosis between them. In this context, a valid measure (e.g. test) for depression should have convergent validity with other tests, be established to assess depression and discriminative validity with tests, designed for assessment of anxiety. In other fields of medicine external criteria for validity are introduced, such as biological measures. No such criteria have been introduced yet in clinical psychiatry. What has been regarded as highly problematic in this sense is the lack of external validators, which refers particularly to discovery and replication of external-tothe- narratives biomarkers that may sustain the claim to diagnose mental disorders as natural kinds and thereby as objects for study and intervention in a traditional bio-medical framework. No such stable biomarkers have been identified to be incorporated into psychiatric diagnosis. Nonetheless such a biomarker should incorporate data from neuroscience. Those data in fact represent what might be assumed as reification in a post-modern sense.

The search for new targets for anticancer therapy development is always ongoing and, because cell proliferation is a central process in carcinogenesis, most of the classical anti-tumor therapeutic approaches have been including antiproliferative agents. However, strong side effects and resistance are commonly reported as responsible for the failure of cancer treatment, so that alternative strategies are needed to achieve more effective drugs. Over the past two decades, the telomeres (nucleoprotein structure at the end of the linear chromosome) have gained attention in the oncology field given that these structures have a crucial role in tumor cells. In fact, engaging a telomere maintenance mechanism is an essential step for carcinogenesis, which often results from the reactivation of the enzyme telomerase. The fact that 85%-90% of all tumors express that enzyme (undetectable in most normal tissues) makes telomerase a very attractive target for new drugs [1]. The structure details of telomerase (just recently accessed) [2-4], as well as the accumulated knowledge regarding telomeres in general, have been leading to the progress towards the development of experimental telomere-based therapies such as antisense technology, ribozymes and telomerase inhibitors [5,6]. On the other hand, telomerase-deficient cancer cells activate a DNA recombination process that drives them into a pathway known as Alternative Lengthening of the Telomeres (ALT) [7], whose mechanism remains elusive. The exploration of each of these mechanisms of telomere maintenance has led to the development of drugs such as Imetelstat (GRN163L), BIBR1532, 6-thio-dG, VE-822, and NVP-BEZ235 [8]. Moreover, there are now many pieces of evidence showing activities of telomerase other than telomere maintenance (non-canonical functions of the enzyme) that increases its potential as a molecular target [9]. Thus, the community of researchers interested in telomere-based approach for cancer therapy has grown significantly, so that a general update on the theme would be welcome. In this sense, the special issue intends to cover the main aspects of telomere based approach, focusing on telomere-related targets and markers in oncology, clinical trials with newest drug prototypes, even as clinical relevance of ALT and non-canonical functions of telomerase.

Bioactive molecules are highly privileged substances with biological activity, therapeutic applications, and thus ultimately promote better health outcomes. Natural and synthetic, two major sources are categorized under bioactive compounds. As such, this special issue comprising five articles is devoted to bioactive molecules and their biological applications in various areas. The first article was originated from the Chapman University, United States by group led Dr. R.K. Tiwari that covers areas related to PEGylation and cell-penetrating peptides and their biological applications [1]. A collaborative consortium led by Prof. Michael D. Wilson from University of Ghana, presented an interesting review article focused on ‘leveraging integrated datadriven approaches to aid in unraveling of leishmanicides of therapeutic potential’ [2]. A plethora of enriched functional genomic, proteomic, structural biology, high throughput bioassay and drug related datasets are currently warehoused in both general and leishmania-specific databases, and all these important points are well described in this article. The next article describes mathematical modeling for pancreatic cancer disease, presented by Dr. Manmeet Rawat from University of New Mexico, United States [3]. The fourth article on ‘inhibition of hemoglobin degrading protease falcipain-2 as mechanism for antimalarial activity of triazole-amino acid hybrids’ was presented by Dr. Shailja Singh’s group based at Jawaharlal Nehru University, New Delhi. The authors reported the antimalarial potential of triazole-amino acid hybrids and their role in the inhibition of cysteine protease falcipain-2 as its probable target [4]. The next article focused on ‘DNA repair and damage tolerance mechanisms in mycobacterium tuberculosis’ by Dr. Indrakant K Singh and his team. This review aims to exploring DNA repair and damage tolerance as an efficient target for drug development by understanding mycobacterium DNA repair and tolerance machinery and its regulation, its role in pathogenesis and survival, mutagenesis, and consequently in the development of drug resistance [5]. The editors of this special issue are grateful to the reviewers for their insightful suggestions and valuable support.

The series of special issues “New experimental and computational tools for drug discovery” is being published by our journal as a tool to bring together in the same melting pot researchers from many diverse areas that use or develop enabling techniques for Medicinal Chemistry. As consequence, the different issues of this series have merged both experimental and computational areas of research such as Computational Chemistry, Bioinformatics, OMICS, Combinatorial Chemistry, Data Analysis, etc. with applications in Medicinal Chemistry and Drug Discovery. These areas include both experimental techniques (LC-MS/MS, FTIR, or NMR, etc.) combined or not with computational methods like Molecular Docking and Machine Learning (ML), etc. The series have published a total of seven special issues until this moment (1-7). The papers included in this number follow the same line and can be summarized as follows: Sabando et al. focused on the extracts from leaves, roots and petioles of Gunnera tinctoria have a reputed therapeutic effect as antitussive, urinary and circulatory remedy according to the Mapuche community. The main objective was to evaluate the endothelial function in vitro, and the preliminary healing action in vivo of a methanol extract of G. tinctoria leaves. The role of the extract in the endothelial- dependent mechanism was determined using human umbilical vein endothelial cells. We also monitored the wound healing activity of the extract in rats on the fourth day of incision. The methanol extract has a high polyphenol content of 516 mg gallic acid equivalent/g dry extract, being the main compounds ellagic acid and their derivatives. The incubation of endothelial cells with the extract did not cause apoptosis or disruption of the endothelial cell monolayer, meanwhile the extract decreased the apoptosis induced by high D-glucose and hydrogen peroxide. There was an increase in the number of fibroblasts and granulation tissue in the treated group with the extract. The formation of new blood vessels was also observed on treated wounds. This study provides scientific evidence on the ethnomedicinal use of G. tinctoria leaves in Chilean folk medicine. The extract improves the endothelial function and shows a potential wound healing activity [1]. Monteiro et al. focused their work on Staphylococcus aureus is a gram-positive spherical bacterium commonly present in nasal fossae and in the skin of healthy people; however, in high quantities, it can lead to complications that compromise health. The pathologies involved include simple infections, such as folliculitis, acne, and delay in the process of wound healing, as well as serious infections in the CNS, meninges, lung, heart, and other areas. Researchers around the world have increased their use of phenolic compounds due to their effectiveness against inflammation, infections, and tumors. This research aims to propose a series of molecules derived from 2-naphthoic acid as a bioactive in the fight against S. aureus bacteria through in silico studies using molecular modeling tools. To obtain the results, a virtual screening of these analogues was done in consideration of the results that showed activity according to the prediction model performed in the KNIME Analytics Platform 3.6, violations of the Lipinski rule, absorption rate, cytotoxicity risks, energy of binder-receptor interaction through molecular docking, and the stability of the best profile ligands in the active site of the proteins used (PDB ID 4DXD and 4WVG). Seven of the 48 analogues analyzed showed promising results for bactericidal action against S. aureus [2]. Carracedo-Reboredo et al. cheminformatics models are able to predict different outputs (activity, property, chemical reactivity) in single molecules or complex molecular systems (catalyzed organic synthesis, metabolic reactions, nanoparticles, etc.). Specifically, Cheminformatics prediction of complex catalytic enantioselective reactions is a major goal in organic synthesis research and chemical industry. Markov Chain Molecular Descriptors (MCDs) have been largely used to solve Cheminformatics problems. There are different types of Markov chain descriptors such as Markov-Shannon entropies (Shk), Markov Means (Mk), Markov Moments (πk), etc. However, there are other possible MCDs that have not been used before. In addition, the calculation of MCDs is done very often using specific software not always available for general users and there is not an R library public available for the calculation of MCDs. This fact, limits the availability of MCMD-based Cheminformatics procedures. In this work, we developed the first library in R for calculation of MCDs. We also report here the first public web server for the calculation of MCDs online. In addition, we also compiled a desktop version of the software for offline use. These tools called MCDCalc include the calculation of a new class of MCDs called Markov Singular values SVmax. We also report the first Cheminformatics study of a set of enantioselective organic reactions using the new class of indices. Not only enantioselectivity but a study of biological activity has also been investigated. First, we studied the enantiomeric excess ee(%)[Rcat] for 324 α-amidoalkylation reactions. These reactions have a complex mechanism depending on various factors. The model includes MCDs of the substrate, solvent, chiral catalyst, product along with values of time of reaction, temperature, load of catalyst, etc. We tested several Machine Learning regression algorithms. The Random Forest regression model has R2 > 0.90 in training and test. Secondly, the biological activity of 5644 compounds against colorectal cancer was studied. We developed very interesting model able to predict with Specificity and Sensitivity 70-82% the cases of preclinical assays in both training and validation series. The work shows the potential of the new tool for computational studies in organic and medicinal chemistry [3]. Nocedo et al. infection diseases are illness caused by different microorganisms, such as bacteria, among those caused by resistant bacteria are associated with greater morbidity, mortality and cost of the treatment than those caused by sensitive bacteria of the same species. Thus, the need to find new antimicrobial agents to cope with this phenomenon increases. In this sense, the exploration to natural plants is valuable. Natural products from plants could be interesting alternatives. Some plant extracts and phytochemicals are known to have antimicrobial properties, and can be of great significance in therapeutic treatments. We carried out the study of biological activities of Cissus incisa, taking account its traditional use. Three extracts were prepared from the leaves of this plant: hexane, chloroform methanol; (1:1) and aqueous. Their antibacterial and antitubercular activities were evaluated using microdilution and alamar blue assays; respectively. The chloroform/methanol extract (1:1) was the most active of the three tested extracts for antimicrobial activity. In this way, the extract exhibits a broad spectrum of antimicrobial activity, against the Gram positive and Gram negative bacteria tested, with MIC values between 125 to 500 μg/mL. Until our knowledge, there are no studies to support the traditional use of this plant in relation to the bacterial infection diseases. This research contributes both to the knowledge of the Mexican flora, as well as the discovery of potential antibacterial agents derivate from plants [4]. Santana et al. cheminformatic methods are able to design and create predictive models with high rate of accuracy saving time, costs and animal sacrifice. It has been applied on different disciplines including nanotechnology. Given the current gaps of scientific knowledge and the need of efficient application of food law, this paper makes an analysis of principles of European food law for the appropriateness of applying biological activity Machine Learning prediction models to guarantee public safety. For this, a systematic study of the regulation and the incorporation of predictive models of biological activity of nanomaterials was carried out through the analysis of the express nanotechnology regulation on foods, applicable in European Union. It is concluded Machine Learning could improve the application of nanotechnology food regulation, especially methods such as Perturbation Theory Machine Learning (PTML), given that it is aligned with principles promoted by the standards of Organization for Economic Co-operation and Development, European Union regulations and European Food Safety Authority. To our best knowledge this is the first study focused on nanotechnology food regulation and it can help to support technical European Food Safety Authority Opinions for complementary information [5].

Infections resistance is a global phenomenon that has led to the death of millions of people worldwide. Despite this, therapeutic options for the treatment of these infections are increasingly restricted. For example, only two new classes of antibiotics have been identified and released in the market in the last 20 years (lipopeptides and oxazolidinones). The scenario is even worse as these new classes are to treat infections caused by Gram-positive bacteria whereas the latest antibiotics commercialized for infections caused by Gram-negative bacteria were described in the 1960s. In this sense, fungi are also an important group of pathogens even though fungal infections are neglected by the public health and global health communities. Candida spp. are the most common cause of fungal infections in humans and are classified by the U.S. Centers for Disease Control and Prevention (CDC) as a serious threat to human health due to its increasing resistance to antifungal drugs. Antiviral drug resistance is an increasing concern in immunocompromised patient populations, where ongoing viral replication and prolonged drug exposure lead to the selection of resistant strains. Rapid diagnosis of resistance can be made by associating characteristic viral mutations with resistance to various drugs. The emergence of viral resistance against any specific and potent drug is virtually inevitable. There is an urgent need to clarify the most effective use of antiviral resistance assays in clinical practice. This special issue was divided into two parts and, in this 2nd part, 6 manuscripts were selected dealing with recent advances application of some compounds as sulfonamides, quinones, pyrimidines, quinolones and inhibitors of dipeptidyl peptidase-4 in the treatment of drug-resistant infection. de Oliveira et al. [1] investigated the antioxidant and antibacterial potential of sulfonamides derived from carvacrol, a small molecule with drug-like properties. Most sulfonamides had antioxidant and antibacterial potential, especially compound S-6, derived from beta-naphthylamine. To understand the possible mechanisms of action involved in biological activity, the experimental results were compared with molecular docking data, for an appropriate discussion on the identified structure-activity relationships. de Oliveira et al. [2] showed the investigation of the antioxidant and antifungal behavior of dimeric naphthoquinones derived from lawsone evaluated against seven fungal strains. The antioxidant potential was tested using the combination of the methodologies: reducing power, total antioxidant capacity and cyclic voltammetry. Molecular docking studies (PDB ID 5V5Z and 1EA1) were conducted which allowed the derivation of structure-activity relationships (SAR). The compound 3- methylfuran-2-carbaldehyde showed the highest antifungal potential with an emphasis on the inhibition of Candida albicans species (MIC 0.5 μg/mL) and the highest antioxidant potential. Leite et al. [3] described the synthesis of a series of 1H-indole-4,7-dione derivatives in good yields by reaction between bromoquinone and β-enamino ketones copper(II)-mediated. Several indolequinone compounds showed an effective antimicrobial profile against Gram-positive (MIC 16 μg.mL-1) and Gram-negative bacteria (MIC 8 μg.mL-1) similar to antimicrobials present in the market, in vitro antimicrobial evaluation, and in silico analysis. These results highlighted 3-acetyl-1-(2- hydroxyethyl)-1H-indole-4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Pantaleão et al. [4] reported a study that investigated the main interactions between DPP-4 and a set of inhibitors, as well as to propose potential candidates to inhibit this enzyme for the treatment of type II diabetes mellitus. For this, the authors performed molecular docking studies followed by the construction and validation of CoMFA and CoMSIA models. The information provided from these models was used to aid in the search for new candidates to inhibit DPP-4 and in the design of new bioactive ligands from structural modifications in the most active molecule of the studied series. From the protocol employed in this study, they were able to propose a set of analogs with biological activity predicted by the CoMFA and CoMSIA models, suggesting that our protocol can be used to guide the design of new DPP-4 inhibitors as drug candidates to treat diabetes. Pimentel et al. [5] could predict that PAP derivatives can be further exploited because they may provide highly selective ATP-competitive TKIs that are active in the nanomolar or picomolar range. Thus, the ATP-binding site of PTKs is an attractive target for the design of anticancer drugs. As a result, many TKIs with interesting in vitro and in vivo profiles are undergoing preclinical and clinical evaluation and are expected to enter the market in the coming years. Batalha et al. [6] provide a compilation of some of the major studies published in recent years showing the discovery and/or development of new antiviral oxoquinoline agents, highlighting, whenever possible, their mechanisms of action.All these publications (part 1 and 2) confirm the importance of new developments in the medicinal chemistry targeting drug-resistant infection.

The search for new drugs capable of reducing or eliminating the morbidity, mortality and suffering of patients affected by various diseases has been one of the main focuses of medicinal chemistry. The need to increase drug dosage to maintain the desired pharmacological effects can result in drug resistance from changes in the target organism - most frequently in infectious diseases. Drug resistance is defined as a reduced susceptibility to a drug in a laboratory culture system and can lead to a complete loss of drug efficacy because the target organism no longer responds to pharmacological doses. With the advent of drugs that could treat infectious diseases, the era of infectious diseases was declared over in the 1970s. Unfortunately, shortly thereafter more and more drug resistance was noted in an ever increasing number of infectious diseases. This special issue was divided into two parts and, for this first part, were selected 8 manuscripts dealing with recent advances in nanoparticles, quinolines, flavonoids, triazoles, quinones, lactones and coumarins for the treatment of drug-resistant infection. Zou et al. [1] described the preparation of PTX surface decoration of silver nanoparticles. Ag@PTX significantly increased the population of A549 cells. The underlying molecular mechanisms of the study revealed that cell death A549 reduced by Ag@PTX was due to cell apoptosis. Ag@PTX induced caspase-3 mediated apoptosis through ROS generation, including AKT and p53 signaling pathways. The in vivo experiments showed that injection of mice with Ag@PTX effectively inhibited tumor growth. Therefore, this study provides the possibility of using a nanosystem to induce A549 cell apoptosis and offers a new strategy for potential cancer therapy. Rogerio et al. [2] prepared 19 quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives connected by a linker group to quinoline ring moieties with different substituents which were assayed against chloroquine-resistant Plasmodium falciparum, along with the reference drug chloroquine. Among these compounds, the derivatives with two methylene carbon spacers showed the best activity accompanied by low cytotoxicity. The extraordinary decrease in cytotoxicity (200-500 times less cytotoxic) of these two compounds compared to the parent compounds, while maintaining or even increasing antiplasmodial activity, make them promising candidates for future research. Freitas et al. [3] demonstrated that the neuraminidase (NA) activity of wild-type and OST-resistant influenza virus was inhibited by agathisflavone, with IC50 values ranging from 20 to 2.0 μM, respectively, and inhibited the influenza virus replication with an EC50 of 1.3 μM. The authors concluded that agathisflavone and its target region in the influenza virus NA represent respective promising chemical structure and pharmacological insight for further development through medicinal chemistry. Novais et al. [4] showed the preparation of bis(2-hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes catalyzed by L-aminoacids in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including hospital nethicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) guidelines mainly against P. aeruginosa ATCC 27853 (MIC 8-128 μg/mL) and MRSA (MIC 32-128 μg/mL). All derivatives had no hemolytic effects on healthy human erythrocytes. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics. Sacramento et al. [5] reported that the compound 4-(4-phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl, inhibited the NA activity of WT and oseltamivir-resistant strains of influenza A and B virus at the nanomolar range. This results suggest that this chemical structure is a promising one for the development of novel antivirals against influenza. Alves et al. [6] established a novel synthetic route to chiral spiro-γ-lactams. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 μM) were identified. The studied β- and γ- lactams were not cytotoxic and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. The observed results suggest that the β-lactam core is a requirement for activity against both HIV and Plasmodium. Francisco et al. [7] prepared eleven coumarin derivatives and evaluated them as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that compounds 5c, 5d, and 6b inhibited GSK-3β enzymatic activity by 39.0-49.6% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 μM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.22-6.88 μM) values, except for compound 7c (IC50 10.81 μM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3β inhibitors. Silva et al. [8] showed the synthesis of eight new gingerol triazole derivatives by CuAAC and the results presented here showed that compound 1 exhibited low cytotoxicity against MCF-7 and HCT-116 cell lines. However, by utilizing the structural potential of this substrate as a prototype for obtaining novel biological agents, the authors observed a notable improvement in the percentage of cell growth inhibition. This was most evident in the assay using MCF-7 cells, where most synthesized compounds inhibited cell growth by more than 70%, with most effectiveness reaching 87% at 50 μM. In this first part, we hope that the selected reviews for this special issue will motivate, inspire and promote the research for the development of new prototypes of drugs containing coumarin scaffolds.

Drug discovery and development focuses on revolutionary breakthroughs and developments in the fields of life sciences and biotechnology. The disciplines related to drug discovery are becoming increasingly closely intertwined. New approaches and technologies such as gene editing, tumor immunotherapy, biological big data and artificial intelligence are emerging and bring new opportunities and challenges to this field. Thus, the application of new techniques and approaches have become a very hot topic in drug design, drug target discovery and disease treatment. This special issue will focus on various aspects of the development and application of techniques in drug discovery and development. In this collection, there are four interesting papers covering drug research relating to peripheral artery disease, Type 2 diabetes mellitus, Alzheimer's disease (AD), anesthesia and nature products. Alzheimer's disease (AD) is a chronic neurodegenerative disease that is widespread in the elderly. Although several efforts have been made in the past two decades, the pathogenesis of AD is still elusive and so far there is no effective prevention and treatment. In this collection, Xie et al. summarized the main drug targets against AD including acetylcholinesterase (AChE), amyloid-beta binding alcohol dehydrogenase (ABAD), butyrylcholinesterase (BChE), β-site APP cleaving enzyme 1 (BACE1), cyclin-dependent kinase-5 (CDK-5), glycogen synthase kinase-3β (GSK-3β); monoamine oxidase (MAO) and tau protein [1]. Type 2 diabetes mellitus (T2DM) is a complex progressive disease with serious life-threatening complications. Insulin secretion promoting agents are important oral drugs for the treatment of T2DM. Professor Lu et al. introduced the research history and the latest progress of sulfonylureas and glinides as insulin secretagogues. The mechanism, characteristics, efficacy and side effects of the drugs were discussed with sufficient details, which provided valuable information for further research, development and application of the drugs [2]. Pyrola (Pyrolaceae) herbs, a well-known Chinese herbal medicine (named Luxiancao or Luhancao), has been used historically as a tonic, anti-inflammatory and antioxidant agent for thousands of years. In Yang et al.’s review, they aim to summarize previous and current references regarding botany, traditional use, phytochemistry as well as pharmacological activities and safety of Pyrolaherbs. It would provide insights into potential opportunities for future research and development of this plant [3]. Continual technological progress of cardiopulmonary bypass (CPB) significant spurs the advancement of cardiac surgery. An oxygenator with integrated arterial filters (IAF) is expected to be more beneficial to the patients with low body weight when using a minimized extracorporeal circulation system. Wang et al. discussed briefly concept of integration, current oxygenators with IAF, and in-vitro / in-vivo performance of the oxygenators with integrated arterial filters (IAF) [4].

Targeting for Human Diseases: Recent Advance – PART I

“Current Topics in Dentistry”, a special issue of “Current Topics in Medicinal Chemistry”, aims to cover all the latest outstanding developments in dentistry. This special issue has the purpose to describe interdisciplinary fields that combine the principles of medical and material sciences, towards the development of therapeutic strategies in dentistry. The aim of this issue is to yield the development of new treatment opportunities in dentistry. The objective of this special issue is to present some research underlying new diagnostic and therapeutic methods useful in dentistry and, in the current scenario, challenges and perspectives in dentistry. The growth of pharmaceutics and biomaterials as a research field has provided a novel set of therapeutic strategies for dental applications. The knowledge that has arisen from studies in the dental area may translate into new methods for caring or improving the alternatives used to treat patients in daily clinics [1, 2]. So we hope that Current Topics in Dentistry will be useful both for researchers and dentists to have a global view of the most recent advances in dentistry.

Studies of ADMET Properties in Medicinal Chemistry – Part-II

In recent decades, the identification of thousands of lead compounds, through development of analytical, synthetic, and computational techniques has occurred. However, the path followed by a bioactive compound to become a drug is long and involves differing methodologies. Different variables must be considered, such as pharmacokinetics, drug interactions, efficacy, safety, among others. The process is long and expensive [1]. In pharmaceutical studies, pharmacokinetic properties (absorption, distribution, metabolism, excretion and toxicity (ADMET). In recent decades, ADME properties turn out to be the main factors that cause the failure of bioactive compounds candidate for new drugs. Yet during the development of bioassay techniques, biotech methods, bio- guided phytochemical studies, automated high throughput screening, and high performance analytical methods, have introduced new concepts in the drug research [2-4]. In vitro and/or computational models, allow the study of parameters that influence the pharmacokinetics of the possible future drug. Traditional in vivo studies provide exact pharmacokinetic profiles, including apparent problems in dose variations; but in vitro and in silico work, being increasingly reported in the literature, provides reliable predictions, saves time and expenses, and avoids ethical complications. Through such studies, the researcher identifies development problems, which are low solubility and hence poor bioavailability of orally administered drug and /or formulation problems [5]. Pharmaceutical industries invest many dollars in high-throughput in vitro and in vivo ADME screening. Undesirable pharmacokinetic profiles are soon identified and alternative studies are done to correct the problem. To decrease the time in the process of searching for new drugs increasingly the investigation of characteristics related with structure as permeation, distribution, metabolism, and toxicity; including molecular interactions, tissue permeations, metabolic pathway, etc. [5]. In this issue you will find the mini-review of the Drs. Toropova & Toropov entitled Whether the Validation of the Predictive Potential of Toxicity Models is Solved Task? contains collection of attempts to use for the above-mentioned task, two special statistical indices, which may be a measure of the predictive potential of models. These indices are (i) Index of Ideality of Correlation; and (ii) Correlation Contradiction Index. You will find the interesting paper of the Drs. Kataria & Khatar entitled In-silico designing, ADMET Analysis, synthesis and biological evaluation of novel derivatives of diosmin against urease protein and Helicobacter pylori bacterium. Insilico studies played an important role in designing the potent ligands against urease protein as well as in explaining the binding pattern of designed and synthesized ligand within active pocket of jack bean urease protein. ADMET studies were also carried out to check the drug similarity of designed compounds by the means of quikprop module of molecular docking software. Hence, the present investigation studies will provide a new vision for the discovery of potent agents against H. pylori and urease associated diseases. In the paper Synthesis, biological evaluation and molecular docking studies of novel di-hydropyridine analogs as potent antioxidants of the Drs. Saddala & Pradeepkiran were evaluated for antioxidant activity (DPPH method), metal chealating activity, hemolytic activity, antioxidant assay (ABTS method), cytotoxicity, molecular docking and in silico ADMET properties. dihydropyridine derivatives act as potent antioxidants and metal chealating property which may useful in treating oxidative stress associated diseases. Glutamate is the principal neurotransmitter in the human brain that exerts its effects through ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs are the class C GPCRs which play a vital role in various neurobiological functions, mGluR1 and mGluR5 are the two receptors distributed throughout the brain that involved in cognition, learning, memory and other important neurological processes. Dysfunction of these receptors can cause neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, X-fragile syndrome, anxiety, depression etc., hence these receptors are high profile targets for pharmaceutical industries. In the work of the Drs. Pabhu & Singh, Identification of Potential Dual negative allosteric modulators of Group I mGluR family: A shape based screening, ADME Prediction, Induced Fit Docking and Molecular Dynamics approach against Neurodegenerative Diseases, novel and potent dual negative allosteric modulators for mGluR1 and mGluR5. The article of Dr. Rahman et al, In-silico subtractive proteomic analysis approach for therapeutic targets in MDR Salmonella enterica sub sp. Enterica serovar Typhi str. CT18, report studies made for subtractive proteomic analysis approach for novel drug targets in Salmonella enterica using computational tools. These proteins were further BLAST against approved drug targets in which 7 cytoplasmic proteins showed druggability and can be used as a therapeutic target. Herbal medicine can directly affect hepatocytes leading to hepatoxicity based on both intrinsic and extrinsic factors. The potentiation of the activity of concurrently administered conventional agents is potentially lethal especially if the drugs bear dangerous side effects and have a low therapeutic windows. The review of the Drs. Suroowan & Mahomoodally, Herbal Medicine of the 21st Century: A Focus on the Chemistry, Pharmacokinetics and Toxicity of Five Widely Advocated Phytotherapies, highlighted the: health benefits, pharmacokinetic, interaction and toxicity profile of five globally famous herbal medicines. We, the Guest-Editors, would like to express our gratitude to the many authors who contributed to this special issue, reporting investigations in various aspects of Studies of ADMET Properties in Medicinal Chemistry – Part I.

Candida spp. inhabit as a commensal in various parts of the human body. They usually remain benign. However, they could cause superficial to life threatening diseases particularly in immunocompromised populations. Candida spp.-associated infections have become a major clinical challenge and a substantial economic burden due the emergence of drug resistant strains in recent times. The incidence of invasive and disseminative candidiasis have been on the rise globally, and people with impaired immune system are the most vulnerable. Candida infections are often associated with biofilms, which harbor highly drug resistant persister cells causing failure of antifungal therapy. Such conditions have augmented morbidity and mortality in human populations [1]. In the face of prevailing and continuously evolving drug resistance among Candida spp. against most of the currently used anti-fungal drugs [2], there is a greater need than ever before for the discovery and development of new anti Candida agents which could effectively address the imminent threat of drug-resistance among the target pathogens. Also, such drugs need to be safer with minimum or no adverse side effects on patients. There are some promising new drug candidates in the pipeline for anti-Candida therapy [3]. However, persistent efforts need to continue to explore and discover novel drugs and innovative therapies to contain the still growing menace of candidaemia. In the present thematic issue of Current Topics in Medicinal Chemistry, several authors have thrown light on the current approaches in the discovery and development of drugs and therapies for candidiasis. Silva et al. have presented an excellent overview of the problems of drug resistance in various emerging Candida spp. pathogens. This is an alarming situation indeed that needs urgent and comprehensive attention of all the stakeholders, like scientists, funding agencies and government bodies. Further, the authors have dwelt upon the new anti-Candida drugs, which are at different phases of development, and some of these appear to have excellent potential to prove as desirable drugs. They have also discussed about the cellular targets in the pathogen for the new drugs [4]. Ortiz and Sansinenea have presented the chemistry of anti-Candida drugs that are already in use and also discussed the synthesis of new drugs. Since emergence of resistance against known classes of drugs have become quite common, new drug discovery is essentially the need of the hour. The various schemes and strategies presented in the article may find use in synthesis of new anti-Candida drugs with reduced toxicity and enhanced efficacy [5]. In addition to synthetic drugs, natural products from plants, microbes and other sources present goldmines for exploring new therapeutic compounds to deal with the ever increasing menace of candidemia. Singla and Dubey have presented diverse natural compounds from classes like terpenoids, alkaloids etc., which have shown significant potential to inhibit the biofilm of Candida spp. As biofilm-associated candidiasis poses a serious threat to human health, leads from this work might prove useful in finding an effective inhibitor of biofilms produced by Candida spp. [6]. Kumar et al. have examined the reports on anti-Candida activity of the extracts from different parts of several plants. They have summarized the reports on the bioactive compounds against Candida spp. that have been isolated from various plants. It could be seen that some of these compounds, for example, thymol and carvacrol, interfere with the structural integrity by way of integrating themselves in the lipid bilayer, causing destabilization of the membrane. Some other compounds, like allicin and cinnamaldehyde, could be seen acting on other intracellular process of Candida spp. [7]. In another article on bioactive molecules from natural sources, Wadhwa et al. have discussed how immune- modulation and an immunotherapy approach that could offer effective alternative to anti-Candida drugs and, thus, could also address the challenges of drug resistance in the pathogens. They have further discussed nanoparticle-based drug formulations which have shown promise besides summarizing the current anti-Candida drugs that are under various stages of development [8]. In a subsequent article, Gowda et al. discussed combinational therapy, application of antibodies, photodynamic therapy and use of primed immune cells with emphasis on the development of effective vaccination [9]. In the final article of this issue, Alves et al, have attempted to explore and study different patents that have described drugs and their formulations to treat infections by Candida spp. It is evident from this study that significant work is underway to develop new drugs, their formulations and delivery for improving the effectiveness and efficacy of treatment [10]. However, biofilm-associated candidiasis associated with difficult-to-treat drug resistant pathogens needs far greater attention as biofilm inhibitory agents are expected to enter the clinic sooner rather than later.

Due to their small dimensions (in the range of 1-100 nm), nanomaterials have a large surface area-to-volume ratio and can be surface-engineered to provide functional properties (i.e., biological and chemical reactivities) that the bulk materials do not exhibit. These properties of nanoparticles are becoming key components in the development of novel therapeutic and diagnostic medicine that overpass the limitations of standard approaches (in terms of efficiency and performance). Gold nanoparticles (AuNPs) [1-3], quantum dots (QDs) [4, 5], upconversion fluorescent nanoparticles (UCPs) [6] and superparamagnetic iron oxide nanoparticles (SPIONs) are widely used in nanomedicine and have been widely reported as drug delivery carriers [7], in phototherapy, and as in vivo imaging agents and diagnostic probes. Understanding the surface-modification chemistry of these different classes of nanoparticles with biomolecules (i.e., peptide, protein, DNA, and RNA) is essential for the preparation of functional nanomaterial systems and their application in medicine. The objective for this thematic issue is to report the recent progress and cutting-edge applications of functional nanomaterials in medicine. We present several reviews that discuss the synthesis, modification, and applications of functional nanomaterials and provide a comprehensive summary to guide the design of bio-nanoparticle systems to have improved sensitivity, specificity, accuracy of diseases diagnosis, and effective and targeted therapeutics. Ruan et al. in the article “Functional nanomaterials for the detection and control of bacterial infections”, summarized some recent applications of functional nanoparticles, including metal nanoparticles (Au and Ag), magnetic nanoparticles (magnetite or Fe3O4) and metal nanocomposites, for the diagnosis and treatment of bacterial pathogens with the aim of providing an overview of the most important trends for addressing these two grand clinical challenges. In each section, they firstly discussed the recent developments of functional nanoparticles for bacterial detection. The detection mechanism, sensitivity, selectivity and technological limitations of these nanoparticles are also summarized. Second, they present the inherent antimicrobial activity of different nanoparticles due to their physiochemical properties, such as size, morphology, and surface functionalization, especially when combined with antibiotics. In addition, biocompatibility and toxicity towards nanoparticles are discussed with regard to further improving current designs before clinical applications. Finally, a critical outlook on potential challenges and potential future directions of metal-based NPs for the diagnosis and treatment of bacterial infectious diseases is provided [8]. In the review entitled “Variety of bio-nanogold in the fabrication of lateral flow biosensors for detection of pathogenic bacteria”, Cheng et al. highlighted the current variety of bio-nanogold lateral flow biosensors (LFBs) and their targets, with a special focus on whole-cell and DNA detection of pathogenic bacteria. The challenges of improving the performance and accessibility of bio-nanogold-based LFBs for detecting pathogenic bacteria are also comprehensively discussed [9]. Dr. Zhongjian Chen and Dr. Quangang Zhu provide a comprehensive review of functional nanomaterial based theranostic medicine for melanoma, in the article entitled “Current Progresses of Functional Nanomaterials for Imaging Diagnosis and Treatment of Melanoma”. The latest research progress of nanomaterials in melanoma is presented with regard to prevention, diagnosis and treatment. The purpose of the review was to provide readers with an understanding of the mechanism of action and the applications of nanomaterials in the field of melanoma diagnosis and treatment [10]. In the review “Nanoparticle delivery systems for DNA/RNA and their potential applications in nanomedicine”, Dr. Jian Xiao and co-authors provide a comprehensive summary on the types of nanoparticle systems used for gene delivery. They highlight the current use of nanocarriers in recombinant DNA and RNAi molecules delivery, and the current landscape of genebased nanomedicine—ranging from diagnosis to therapeutics. Additionally, they briefly discuss the biosafety concerns and limitations in the preclinical and clinical development of nanoparticle gene systems [11]. Overall, in this thematic issue, the current progress in the preparation and modification of functional nanomaterials and their applications in theranostic medicine are comprehensively discussed and presented in above mentioned review articles. These topics included functional nanoparticle for bacterial infection detection and control, gene drug delivery systems, cancer theranostic medicine, and point-of-care testing. We believe these interdisciplinary topics will draw broad attention from a broad audience in material science, biomedicine, and engineering, and it will provide a deeper view and understanding of the chemistry behind the biomedical applications of nanoparticles.

In direct contrast to the inhibition of protein functions, the activation is another important strategy drug hunters employ to achieve desired therapeutic effects in their practice. This could be accomplished through a diverse set of pharmacological agents, such as orthosteric agonists, allosteric agonists, and positive allosteric modulators (PAM). While the topic is very broad, we intend to sample protein activation in drug discovery in multiple therapeutic area in different development stages. We also want to highlight some current advances in the recently developed concepts of bitopic and biased activations in the G-protein coupled receptor (GPCR) field. In addition, we are interested in structural insights that could potentially allow design of ligands with better potency and target selectivity. In this thematic issue of Protein Activation in Drug Discovery, three manuscripts encompassing multiple protein classes are presented. Reinecke et al. highlight the recent advances of the promising bitopic agonists/activators for GPCR receptors that were designed to achieve high potency and selectivity and discuss their therapeutic potentials [1]. Sniecikowska et al. describe some recent development of biased agonists of the serotonin 1A receptor (5-HT1A) receptor that could potentially offer improved therapeutic effects without triggering side effects [2]. Hao et al. provide structural insights into the orthosteric ligand binding pocket (LBP) of the metabotropic glutamate receptors (mGluR) and highlights the residues in the LBP that contribute to the group and subtype selectivity for these GPCR class C family receptors [3]. We are grateful to all the authors who contributed to this special thematic issue and referees who provided insightful feedbacks. We also want to thank Dr. Allen B. Reitz (Editor-in-Chief) and Ms. Ambreen Irshad (Editorial Manager) for their help during the preparation of this issue. The success of this issue is not possible without their help.

Inhibition of posttranslational modifications is related to a number of diseases such as cancer, nervous and cardiovascular system diseases. To timely and accurately get target 3D-structures for rational drug design, both theoretical and experimental approaches of structural biology such as PseAAC, PseKNC, graphical approaches, NMR, x-ray crystalography, and cryoelectronic microscopy (Cryo-EM) are used [1-9]. The main goal of this special issue is to report recent progress of drug target research in this area. Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression or NCAM polysialylation is associated with tumor cell migration and progression in many metastatic cancers and neurocognition [10]. However, the specific mechanism(s) and the determinants of migration and the migration mode still remain unclear. In the first review article entitled “A Possible Protein-Protein Interaction Modulation during Neural Cell Adhesion Molecule (NCAM) Polysialylation” [11] by Prof. Drs. Guo-Ping Zhou and Ri-Bo Huang and their coworkers summarized recent research on the intermolecular and intramolecular interactions within the lumen of mammalian cells. Based on these cooperative interactions, a novel model of NCAM polysialylation and cell migration mechanisms have been proposed, which may benefit the design of new inhibitors of NCAM-mediated cancer cell proliferation. Recently, Chou’s pseudo amino acid components are widely and increasingly used in computational biology and have been systematically addressed [12]. In the second review article entitled “Impacts of pseudo amino acid components and 5-steps rule to proteomics and proteome analysis” [13], Prof. Dr. Kuo-Chen Chou described Chou’s 5-steps rule and its influence for developing various predictors in biology and biomedicine. Particularly, impacts on protein structural class prediction, protein subcellular location prediction, and post-translational modifications, as well as their web-servers have been elaborated. Cancer is a major disease which has become the biggest killer of humankind due to the difficulties in its early detection, diagnosis and treatment. Since high-throughput technology including microarrays and next-generation sequencing (NGS) are widely applied in tumor biology, in-depth studies of tumor biology are significantly improved at the genetic and genomic levels. Prof. Bing Niu and his colleagues in their review article titled “Identifying cancer targets based on machine learning methods via Chou’s 5-steps rule and general pseudo components” [14] summarized current machine learning techniques used in the prediction and related studies of cancer by their genetic sequencing data. Meanwhile, using Chou’s 5-steps rule, an efficient work flow was introduced combined with machine learning methods. Subsequently, Professors Jianyong and Qian Han and their coworkers in their review article entitled “A study for therapeutic treatment against Parkinson’s Disease via Chou’s 5-steps rule” [15] further proposed that Chou’s 5-steps could be applied to many disease conditions when considering prevention and treatment strategies, including Parkinson’s disease, HIV/AIDS, etc. Parkinson’s disease is due primarily to the inability of patients to produce adequate level of dopamine in the central nervous system. The disease affects more than 10 million people worldwide and approximately one million in the US alone. In the US, the combined direct and indirect costs are about $52 billion a year. The authors of this review article provide an update regarding the structures, functions, and inhibitors of DDC, particularly with regards to the treatment of Parkinson's disease. This information will provide insight into new pharmacological treatments for Parkinson's disease. The anti-cancer efficacy of ginseng is attributed mainly to the presence of saponins, which are commonly known as ginsenosides. Ginsenosides were first identified as key active ingredients in Panax ginseng and subsequently found in Panax quinquefolius, both of the same genus. To review the recent advances on anti-cancer effects of ginsenosides against breast cancer, the review article entitled “Recent Advances in Ginsenosides as Potential Therapeutics Against Breast Cancer” [16] by Professor Ying Gao and the colleagues conducted a literature study of scientific articles published from 2010 through 2018 by searching the major databases including Pubmed, SciFinder, Science Direct, Springer, Google Scholar, and CNKI. Their review focuses on how ginsenosides exert their anti-breast cancer activities through various mechanisms of action. In summary, recent advances in the evaluation of ginsenosides as therapeutic agents against breast cancer support further pre-clinical and clinical studies to treat primary and metastatic breast tumors. Acetoin is an important four-carbon compound that has many applications in foods, chemical synthesis, cosmetics, cigarettes, soaps, and detergents. Its stereoisomer (S)-acetoin, a high-value chiral compound, can also be used to synthesize optically active drugs, which could enhance targeting properties and reduce side effects. The review article entitled “Biological production of (S)-acetoin: A state-of-the-art review” [17] by Prof. Neng-Zhong, Ri-Bo Huang and their colleague summarized the considerable progress in recent years in the development of biotechnological routes for (S)-acetoin production, including various strategies for biological (S)-acetoin production, and their constraints and possible solutions are described. Furthermore, future prospects for biological production of (S)-acetoin are discussed. Owing to their wide structural diversity and unique complexing properties, cyclodextrins (CDs) find manifold applications in drug discovery and development. The mini-review article entitled “Cyclodextrin Inclusion of Medicinal Compounds for Enhancement of their Physicochemical and Biopharmaceutical Properties” [18] by Prof. Mino R. Caira summarized CD’s used as ‘enabling excipients’ both in the context of early drug discovery and in subsequent optimization of drug performance. The descriptions of the structures of CDs, synthetic derivatisation to fine-tune their properties, the nature of inclusion complexation of drugs within the CD cavity, the inherent pharmacological activity of several CDs and its utility, novel CD-based drug delivery systems, and the role of CDs in drug discovery and optimization are also included. There are many opportunities for the intervention of CDs during early stages of drug discovery, which could guide the selection of suitable candidates for development and thereby contribute to reducing the attrition rate of new molecular entities. As we can see from the aforementioned papers collected in this special issue, both experimental and theoretical studies of drug targets have a high impact on the research of medicinal chemistry.

In direct contrast to the inhibition of protein functions, the activation is another important strategy drug hunters employ to achieve desired therapeutic effects in their practice. This could be accomplished through a diverse set of pharmacological agents, such as orthosteric agonists, allosteric agonists, and positive allosteric modulators (PAM). While the topic is very broad, we intend to sample protein activation in drug discovery in multiple therapeutic area in different development stages. We also want to highlight some current advances in the recently developed concepts of bitopic and biased activations in the G-protein coupled receptor (GPCR) field. In addition, we are interested in structural insights that could potentially allow design of ligands with better potency and target selectivity. In this thematic issue of Protein Activation in Drug Discovery, five manuscripts encompassing multiple protein classes are presented. Chan et al. review the development and potentials of non-peptidyl activators of the insulin-induced and brainderived neurotrophic factor (BDNF)-induced signaling pathways in type 2 diabetes mellitus (T2DM) treatments [1]. Lian et al. summarize both cyclic dinucleotide (CDN) and non-nucleic acid derived STING agonists that have generated enormous interest and been intensely pursued in this new era of cancer immunotherapies [2]. McGowan describes recent developments in the small molecule activation of the Toll-like receptors (TLRs) 7 and 8 in the innate immunity signaling [3]. Goldsmith updates on the activation of N-methyl-D-aspartate receptor (NMDAR) with a diverse chemotypes of positive allosteric modulators (PAMs) that could potentially lead to new treatments in neurological and psychiatric disorders [4]. Atobe reviews recent advances of agonists of transient receptor potential vanilloid (TRPV) and their application as disease-modifying osteoarthritis drugs (DMOADs) [5]. We are grateful to all the authors who contributed to this special thematic issue and referees who provided insightful feedbacks. We also want to thank Dr. Allen B. Reitz (Editor-in-Chief) and Ms. Ambreen Irshad (Associate Editor) for their help during the preparation of this issue. The success of this issue is not possible without their help.

Cancer is the second leading cause of death globally and is estimated to account for 9.6 million deaths in 2018. In other words, about 1 in 6 deaths is due to cancer. These numbers are expected to rise to over 15 million by the year 2035. RAS proteins, including KRAS, NRAS and HRAS, play an important role in cell growth, differentiation, proliferation and survival by regulating diverse cellular pathways. KRAS is known as a human oncogene for over 30 years, and is the most frequently mutated class of Ras family in all human cancers (21.6%), especially with the highest prevalence in pancreatic adenocarcinomas (90%), colorectal cancers (45%) and lung cancers (35%). Therefore, KRAS represents as an intriguing and promising cancer target, and research efforts towards discoveries of new approaches to targeting mutant KRAS are imperative to offer exciting opportunities in pursuit of developing better therapeutics that can benefit cancer patients. Currently, AMG 510, a potent and selective KRAS G12C covalent small molecule inhibitor developed by Amgen, shows good tumor response in a phase I clinic trial for non-small cell lung cancer and colorectal cancer. And a KRAS siRNA molecule also entered into Phase II clinical trials of pancreatic cancer. This issue contains a diverse collection of reviews aiming to provide the intensive quest in developing effective approaches to combat various KRAS-mutant-driven cancers, point out the difficulties, and point the direction for future research. Cheng et al. provide an overview of treatment of KRAS mutant cancers including directly targeting oncogenic KRAS protein by a virtual screening approach to discover novel KRAS inhibitors [1]. Liu presents an overview of the emerging new therapeutic approaches for inhibiting KRAS signaling and blocking KRAS functions including nano-therapeutic approaches, inhibition of KRAS mutation-mediated metabolic pathway, and inhibition of cell cycle regulation. Since KRAS proteins must be associated to the plasma membrane for their function, targeting KRAS plasma membrane localization represents a logical and potentially tractable therapeutic approach [2]. Ye et al. highlight the recent advances in the development of KRAS plasma membrane localization inhibitors including natural product-based inhibitors achieved from high throughput screening, fragment-based drug design, virtual screening, and drug repurposing as well as hit-to-lead optimizations. Inhibition of upstream cell surface receptors (e.g. EGFR inhibitors) results very brief effects due to the rapid development of drug resistance or tumor recurrence, while inhibition of KRAS downstream effectors results in limited clinical efficacy, thereby the combination therapy is essential for the treatment KRAS mutated cancers [3]. He et al. present the recent advance in applications of drug combinatorial therapies for treatment of KRAS mutated lung cancers. Since RNA interference (RNAi) technologies can efficiently eliminate the expression of specific genes, using RNAi molecule to selectively target KRAS and KRAS's synthetic lethal interactions are an effective individualized targeted drug therapy to KRAS mutant cancers [4]. Liu et al. highlight the current status, future perspective and associated challenges in the application of the RNA interference technologies for KRAS. Cancer immunotherapy is a targeted and personalized approach employing either adoptive T cell transfer, vaccines, antibodies, CAR-T cells, immune checkpoint inhibitors or other immunological components to increase therapeutic efficacy while reducing unwanted side effects commonly associated with conventional cancer therapy [5]. In and collegues focuse on current immunotherapeutic developments and advances in both pre-clinical and clinical studies directly or indirectly targeting KRAS via its downstream signal transduction machinery [6]. Pancreatic cancer is a highly malignant tumor with poor prognosis and high recurrence rate and death rate. Since KRAS mutations have been identified in 60% to 90% of pancreatic cancer, Hao et al. specifically highlight the occurrence and treatment of pancreatic cancer harboring KRAS mutations [7]. As the Guest Editor, I would like to thank all the authors for their tremendous effort, dedication, and excellent contribution to this special issue of Current Topics in Medicinal Chemistry. I hope that this issue will serve as a key reference work for medicinal chemists, chemical biologists, cancer biologists and other research investigators engaged in or interested in drug discovery by targeting mutant KRAS.

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Cardiovascular Diseases (CVDs), such as myocardial infarction, arrhythmia, hypertension and atherosclerosis, are one of the leading causes of disability and death globally. Studies have revealed that healthcare dollars spent in CVDs far exceed those in any other disorders, accounting for approximately 17% in annual healthcare expenditures [1]. Despite huge investments in treating people suffering from CVDs, recent trends are still worrisome and the management of cardiovascular health leaves much to be desired. CVD patients also complain that the current available traditional therapies are not equally shared and satisfied, so that there are large variations in outcomes, highlighting an urgent need in cardiovascular drug innovation. Over the past decades, increasing evidence has shown that bioactive small molecules (e.g., noncoding RNAs and protease inhibitors) play critical roles in the occurrence and progression of diverse CVDs. In this special issue, six prominent experts provide general introductions and overviews of their specialized bioactive small molecules contributing to the cardiovascular field, respectively, and the detailed information as follows: Zhou et al. is dedicated to chemical structure, pharmacodynamic, pharmacokinetic and adverse effects of ivabradine [2]. Ivabradine is a typical inhibitor of the cardiac pacemaker "funny" (If) current. Several completed clinical trials have found that administrations of ivabradine in people with Chronic Heart Failure (CHF) significantly reduces heart rate and improves symptoms by prolonging the slow spontaneous phase in diastolic depolarization. Nonetheless, much more studies need to be carried out to evaluate the therapeutic potential of ivabradine in CHF. Additionally, the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress, is described fully by Zhang et al. [3]. Emerging evidence has established that the UPR activated by acute or chronic disturbance in cardiomyocytes is implicated in the initiation and progression of various CVDs. Hitherto, existing UPR modulating strategies that are being tested in clinical trials all revolve around core proteins, and some exhibit satisfactory results. The last paper contributed by Yan et al. depicts the intimate correlation between microRNA (miRNA) and CVDs [4]. The authors focus on several cardiac-specific miRNAs (e.g., miR-1 and miR-208) as well as widely expressed miRNAs that play significant roles in cardiac development (e.g., miR-15 and miR-21), and elucidate their functions in CVDs. Moreover, therapeutic strategies and challenges to mimic or silence miRNAs in vivo are discussed in the paper. Finally, I want to thank Bentham Science Publishers, especially, Associate Editor, Ms. Ambreen Irshad, who provided me the opportunity to organize this thematic issue and also all the editorial members for their continued support. I express my highest gratitude to all the contributing authors for their professional work and all the reviewers for their evaluations and many valuable suggestions to further improve the manuscripts.

Cardiovascular Diseases (CVDs), such as myocardial infarction, arrhythmia, hypertension and atherosclerosis, are one of the leading causes of disability and death globally. Studies have revealed that healthcare dollars spent in CVDs far exceed those in any other disorders, accounting for approximately 17% in annual healthcare expenditures [1]. Despite huge investments in treating people suffering from CVDs, recent trends are still worrisome and the management of cardiovascular health leaves much to be desired. CVD patients also complain that the current available traditional therapies are not equally shared and satisfied, so that there are large variations in outcomes, highlighting an urgent need in cardiovascular drug innovation. Over the past decades, increasing evidence has shown that bioactive small molecules (e.g., noncoding RNAs and protease inhibitors) play critical roles in the occurrence and progression of diverse CVDs. In this special issue, six prominent experts provide general introductions and overviews of their specialized bioactive small molecules contributing to the cardiovascular field, respectively, and the detailed information as follows: A hepatic protease Proprotein Convertase Subtilisin-Kexin type 9 (PCSK9) serves as an ideal target to treat patients with hypercholesterolemia. Promising PCSK9 inhibiting strategies are summarized in the paper [2], including applications of antisense oligonucleotides, small interfering RNAs, monoclonal antibodies and several small chemical compounds. Notably, alirocumab and evolocumab, two monoclonal antibodies, have gone through clinical trials and been approved by the Food and Drug Administration (FDA) in 2015. Also, the potential use of PCSK9 inhibitors in other internal diseases beyond hypercholesterolemia is discussed. Liu et al. explore cardioprotective effects of bioactive molecules involved in glucose metabolism [3]. Sodium Glucose Cotransporter (SGLT2) is one of three members of glucose transporters identified so far, which plays an essential role in renal glucose reabsorption. SGLT2 inhibitors can reduce the long-term Major Adverse Cardiac Events (MACEs) in diabetic patients sharply. Therefore, there is a bright future of applying SGLT2 inhibitors to prevent the occurrence of MACEs in diabetic patients. Fu et al. summarize current knowledge and progress of the Natriuretic Peptide (NP) system in heart failure, which consists of three distinct members—Atrial Natriuretic Peptide (ANP), B-type Natriuretic Peptide (BNP) and C-type Natriuretic Peptide (CNP)—in mammals [4]. The authors first give a comprehensive discussion of synthesis, degradation and biological functions of these three NPs. All these NPs exert their cardioprotective effects during heart failure by inhibiting the Renin–Angiotensin– Aldosterone System (RAAS) and the sympathetic nervous system. Innovative therapeutic strategies based on modulating the NP system, such as Neutral Endopeptidase (NEP)-resistant NPs and NEP inhibitors, are then introduced in the paper, as well as limitations to circumvent or overcome. Finally, I want to thank Bentham Science Publishers, especially, Associate Editor, Dr. Ambreen Irshad, who provided me the opportunity to organize this thematic issue and also all the editorial members for their continued support. I express my highest gratitude to all the contributing authors for their professional work and all the reviewers for their evaluations and many valuable suggestions to further improve the manuscripts.

Strategies and Tactics in Medicinal Chemistry

In early 1981 a new disease epidemic was reported by the CDC (Centers for Disease Control and Prevention) [1] which was later termed as AIDS (Acquired Immunodeficiency Syndrome) and subsequently, it was identified that the disease is caused by the retrovirus HIV (Human Immunodeficiency Virus) [2]. Since then, scientists from all over the world joined forces to find an effective treatment for the disease and in 1987 the first anti-HIV drug called AZT (azidothymidine) or zidovudine was approved by U.S. FDA (Food and Drug Administration). Within 10 years of discovery of the first antiretroviral drug, the most effective treatment for AIDS was developed, a multidrug combination therapy, widely known as HAART (highly active antiretroviral therapy) or cART (combination antiretroviral therapy) [3]. More than 30 drugs have been invented until now and are being used in different combinations depending on patient response to treatment [4]. Although, the decline of HIV related deaths from a peak of 1.9 million [1.4 million–2.7 million] in 2004 to 940,000 [670,000-1.3 million] in 2017 was achieved through the use of HAART, there are still limitations associated with this treatment such as viral resistance to drugs, toxicity and adverse side effects of drug use and long term drug compliance [5]. Therefore, to overcome all these complexities of antiretroviral treatment, novel drug development with intense clinical study is required. In this thematic issue, the advancement of antiretroviral therapy over the years, their limitations and development of novel drug formulations or regimen to address the limitations has been outlined in details. Antiretroviral therapy (ART) is the HIV medication that reduces the overall viral load and suppresses the probability of acquiring opportunistic infection. ART is not a cure for HIV infected patients, but it increases the life expectancy of patients to facilitate their healthy survival. ART has different combinations of drugs and Protease inhibitor is one of the important constituents among them. Protease inhibitor impedes the HIV-1 aspartyl protease and blocks mature virion formation. In the review entitled “Protease Inhibitors for the Treatment of HIV/AIDS: Recent Advances and Future Challenges”, Dr. Chandrashekhar Voshavar have discussed the recent development of novel small molecule-based inhibitors, their essential pharmacokinetic properties, and application in HAART on the horizon for targeting HIV-1 protease [6]. The review “Recent Progress in the Development of HIV-1 Entry Inhibitors: From Small Molecules to Potent Anti- HIV Agents” summarizes the advancement of HIV-1 entry inhibitors including new drug formulations and variations in the lead compounds for the development of novel inhibitors to increase ART treatment efficacy. HIV-1 entry inhibitors block one of the three steps of HIV invasion into host cells- attachment through CD4 receptor binding, association of co-receptor such as CCR5 and CXCR4 and finally the fusion process. Dr. Suttisintong and co-authors highlighted the computational modeling and structural modification approaches used for the development and screening of newer class of HIV-1 entry inhibitors to increase the potency and effectiveness of HIV treatment [7]. Dr. Maeda et al. in the article “Discovery and Development of anti-HIV Therapeutic Agents: Progress Towards Improved HIV Medication” discussed the discovery process of different types of inhibitors used in cART incorporating the FDA-approved anti HIV drugs and the improvement of the Quality Of Life (QOL) of patients. It also shines a spotlight on the future direction for the identification of novel treatment strategies and targets to overall block the HIV replication in host cells [8]. The envelope glycoprotein gp120 plays an important role in membrane fusion process of HIV host cell entry. Gp120 acts as a key player in the HIV life cycle as its interaction with CD4 triggers membrane fusion and one of its hypervariable loops help HIV to preferentially target T-cell or macrophages. Therefore, targeting gp120 for antiretroviral therapeutics has been a prime focus for researchers to prevent fusion of HIV with host cells. In the article “The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry-a Review” Dr. Motati and co-authors have specifically elaborated the design and synthesis of biologically active class of oxalamide and pyrrole-containing compounds as potential inhibitors for gp120 [9]. Overall, the thematic issue focuses on the recent development of different approaches and strategies implicated to identify novel small molecule antiretroviral drugs for HIV treatment. We, as the Guest Editors would like to extend our sincere gratitude and appreciation to all the authors for their valuable contribution in this thematic issue.

Cancer involves various signaling pathways with uncontrolled cell growth. Notably, according to the World Health Organization, cancer is the second leading cause of death, responsible for 1 in 6 deaths globally. In year 2018, about 9.6 million deaths were due to cancer. Without understanding the cause and its progression mechanism, finding effective treatment is tough. Available chemotherapy, radiotherapy and surgery have their own limitations in cancer treatment. It is difficult to understand cancer comprehensively and especially what is the real cause of cancer. Drug discovery for cancer is one of the hot topics for several decades. As cancer is one of the complex diseases therefore multiple approaches to understand and cure this disease needs to be carried out in parallel. This issue discusses anti-cancer peptides [1], enzymes as targets [2], metabolites [3], repurposing of drug [4], combinatorial therapy, treatment using vaccines, modern technologies and new approaches for cancer treatment. Further, this issue provides a platform for narrating more than hundred years of research of cancer biology and its therapeutics including the achieved milestones. Moreover, this will help to accelerate cancer research [5]. Cancer therapeutics has seen the journey from nitrogen mustard to the more recent kinase inhibitors, antimitotic drugs and monoclonal antibodies. The role of changes in protein and DNA expression, microRNA and small interfering RNA (siRNA) are also discussed. Important information has been collected on tumor suppressor genes, oncogenes, proto-oncogenes, growth factors, and kinases including tyrosine kinases that play a role in cancer. Modern techniques including genomics, proteomics, and metabolomics can be used for the early detection of cancer. Natural small molecules are privileged in anti-cancer drug discovery as most of drugs are small molecules either purified from natural sources such as plants, bacteria, fungi, terrestrial and marine animals or synthesized in the laboratory. Natural bioactive peptides isolated from plants and animals and synthesized analogues have great potential for the discovery of new therapeutics for cancer. Peptides can be used as an adjuvant in combination with other anticancer drugs. As development of new drugs is a very long process therefore repurposing of drugs is a good option. The drugs approved for different causes including calcium channel blockers, antibiotics, antimalarial and anti-inflammation can be repurposed for cancer including retinoblastoma. An enzyme acid ceramidase (ASAH1) is a good target to develop the anticancer drug as ASAH1 converts pro-apoptotic ceramide to anti-apoptotic sphingosine. ASAH1 and its modulator can play an important role in controlling cancer progression and metastasis. Cell metabolism is one of the important areas of concern in cancer progression and metastasis. Malignant cells cause alteration in energy metabolism, lipid composition and several metabolic pathways. Metabolites expressed in the cancer cell can be used as biomarkers for cancer including 2-hydroxyglutarate. These cancer related metabolites or onco-metabolites can be detected using mass spectrometry in body fluids and tissue at different stages of cancer including brain cancer.

G-protein coupled receptors (GPCRs) are a class of seven-transmembrane proteins that have attracted tremendous interest in both the pharmaceutical industry and academia for decades owing to their physiological and therapeutical importance and accessibility for small molecule drug discovery. GPCRs play critical roles in physiological responses to a variety of stimuli such as ions, small molecules, macromolecules, peptides and other proteins, which are associated with the vast biological functions mediated by GPCRs. Aspects of cognition, immune response, and cellular organization as well as many others, are regulated by GPCR signaling. The pharmacological regulation of GPCRs provides leverage for the treatment of various human diseases including those of the central nervous system (CNS), cancer, viral infections, inflammatory disorders, metabolic disorders, and others. Moreover, the location of GPCRs in the cellular membrane allows unique pharmacological access to these proteins while the effectors and second messenger systems coupled to the receptors allow for efficient drug action and drug targeting in the discovery of novel therapeutics. Intriguingly, GPCRs represent the largest family of druggable proteins in the human genome and unsurprisingly are targeted by more than 30% of marketed drugs worldwide. This issue contains a diverse collection of reviews covering the cutting-edge biology and medicinal chemistry in GPCR drug discovery, with special attention to new approaches in traditional targets, emerging targets, and future trends. As a traditional drug target, the dopamine D1 receptor (D1R) is essential to neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Recent chemistry breakthroughs and innovative approaches to selectively target and activate the D1R also holds promise for creating pharmacotherapy for several neurological diseases. Allen and colleagues provide an overview of the major classes of D1R selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive allosteric modulators, highlighting their structure activity relationships and medicinal chemistry [1]. An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR), another traditional drug target in class A GPCRs, contributes to the neurobehavioral processes that underlie addictive disorders as well as other chronic health issues (e.g., depression, impulsivity disorders, obesity). The recently solved crystal structures of 5- HT2CR co-complexed with ligands are expected to significantly facilitate small molecule drug discovery by targeting this receptor. Zhou and colleagues highlight the biological significance, the biological context for signaling and function, as well as the current status of emerging approaches developing various agonists and positive allosteric modulators (PAMs) of the 5-HT2CR [2]. The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor (PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of GPCRs. Enhancing PAC1R signaling has the potential to mitigate cellular damage associated with cerebrovascular trauma (including stroke), neurodegeneration (such as Parkinson’s and Alzheimer's disease) or peripheral organ insults. Given the diverse PAC1R-mediated biological activities, the receptor has emerged as a relevant pharmaceutical target. Li and colleagues provide a comprehensive review on targeting the PAC1 receptor for neurological and metabolic disorders, and highlight the opportunities and insights to accelerate structurebased drug design for PAC1R and other class B GPCRs in the treatment of a number of disease conditions [3]. The cannabinoid receptor 1 (CBR1) is involved in a variety of physiological pathways and has long been considered an important therapeutic target for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R ligand rimonabant, with therapeutic use for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Zhang and colleagues present the recent progress towards overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists, and highlight the current approaches for therapeutics development by targeting this receptor [4]. Type II diabetes is a major health issue worldwide with complex metabolic and endocrine abnormalities. Insulin signaling regulates metabolic homeostasis by regulating glucose and lipid turnover in the liver, skeletal muscle and adipose tissue. Vasudevan and Gupta summarize the emerging antidiabetic therapeutics including classes of drugs targeting GPCRs in the liver, adipose tissue and skeletal muscle, and highlight several shared intermediates between insulin and GPCR signaling cascades opening potential novel avenues for diabetic drug discovery. Adenosine receptors (AR) are a class of purinergic GPCRs. Alterations of AR function and expression have been studied in neurological diseases such as epilepsy, Alzheimer’s disease, and Parkinson’s disease, cardiovascular diseases, cancer, and inflammation and autoimmune diseases [5]. The positron emission tomography (PET) imaging probes have provided valuable information for diagnosis and therapy of diseases related to alterations of AR expression. Chen and colleagues provide a concise overview of various AR-tageted radioligands for PET imaging in diseases, and highlight the most recent advances in PET imaging studies by using AR-targeted probes. Recent success in immunotherapy has advanced cancer treatment from traditional chemotherapy, irradiation therapy and targeted therapy into an exciting new era, representing a promising future trend in cancer drug discovery and development [6]. The discovery of more targets that regulate the immune system and chronic inflammation, such as GPCRs, offers novel alternative strategies for enhancing antitumor immunity. Chen and colleagues provide an update on recent advances in small molecular regulators targeting GPCRs that are associated with oncology immunomodulation, including chemokine receptors, purinergic receptors, histamine receptors, prostaglandin E receptor EP4 and opioid receptors. In addition, they outline how such modulators affect tumor immunity and neoplasia by regulating immune cell recruitment and modulating tumor stromal cell biology, and highlight the recent clinical advances in small molecular regulators targeting these GPCRs, in combination with immune checkpoints blockers such as PD-1/PDL-1 and CTLA4 inhibitors for the treatment of human cancers [7]. As the Guest Editors, we would like to thank all the authors for their tremendous effort, dedication, and excellent contribution to this special issue of Current Topics in Medicinal Chemistry. We hope that this issue will serve as a key reference work for medicinal chemists, chemical biologists, structural biologists, pharmacologists, and other research investigators engaged in or interested in GPCR drug discovery and development.

New drug screening is an important step for drug research. The key point that establishs a new drug screening system for diseases is to search for drug targets based on research on mechanism of action. The interaction of drugs and target proteins plays an important role in the process of disease prevention and control. In recent decades, with the development of molecular biology, human genomics, proteomics and other life sciences and technologies, more and more drug targets have been discovered. In view of the important value and role of drug target proteins, it is necessary to revisit the advance of some important target proteins. The review entitled “Recent progress in the development of small molecule c-Met inhibitors” summarized the progress of the small molecule c-Met inhibitors in the last two years which focused on the rational design, synthesis and structure-activity relationship analysis (Peng-Cheng Lv, et al.) [1]. Duan and co-authors considered the tubulin-colchicine binding site agents including not only inhibitors but also antibody-drug conjugates and degraders (Targeting tubulin-colchicine site for cancer therapy: inhibitors, antibody-drug conjugates and degraders, Yongtao Duan, et al.) [2]. Because of the important role of STAT3, Dr Liu and his group presented the current state of research on STAT3 (Inhibitors Targeting STAT3 with activity of Anti-tumor and Inflammation, Yangsheng Hu, et al.) [3]. Another review from the current issue prepared by Dr Deora emphasized the isolation, synthesis and structure-activity relation of estrogen receptor α (ER)-targeting compounds and derivatives (Estrogen receptor α (ER)-targeting compounds and derivatives: Recent advances in structural modification and bioactivity, Weiyun Guo, et al.) [4]. A receptor tyrosine kinase belonging to the TAM family, Axl, is associated with promoting chemotherapy resistance and tumor cell proliferation. The conclusion of progress of Axl inhibitors would guide pharmaceutical chemists to discover more promising Axl inhibitors in the future (Research progress of Axl inhibitors, Zhigang Sun, et al.) [5]. Immunotherapy is gaining popularity for cancer therapy, and we believe that the topic of epigenetic enzymes in macrophages would attract those involved in biochemical and pharmaceutical research (Epigenetic enzymes in macrophages: a promising drug target for inflammation-associated disease, Pei Sun, et al.) [6]. The breadth of articles in this issue cover a broad spectrum. These papers exemplify a variety of different kinds of targets. I look forward that the readers will enjoy reading these articles.

Lymphatic filariasis (LF), commonly known as elephantiasis is a neglected tropical disease (NTD) caused by Wuchereria bancrofti, Brugia malayi and B. timori. It has been ranked as the second leading cause of long-term chronic disability world-wide. Around 856 million people from 52 countries worldwide are at risk by LF and seek prophylactic treatment to control the expansion. This disease affects the poorest populations who are living in areas with poor sanitation and housing, causing chronic manifestations such as hydrocele, lymphoedema and elephantiasis associated with impaired mobility and social activity, reduced work capacity, sexual dysfunction, severe psycho-social problems, stigma and bad marital prospects. In this regard, the World Health Organization launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF) using diethylcarbamazine (DEC) or ivermectin (IVM) or albendazole alone or in combinations and the results were encouraging as out of 72; twenty countries successfully reduced the infection prevalence to such a level that transmission will not be sustainable. However, due to serious technical difficulties the programme is facing problems in the eradication of this endemic disease as DEC and IVM both are microfilaricides with poor or no activity on adult parasites. Furthermore, resistance has also emerged against albendazole and ivermectin. This depressing perspective demands, an urgent need of intensive drug discovery to develop new, more effective, affordable and accessible macrofilaricidal possessing novel modes of action, which could reduce the time and burden of drug resistant. In this thematic issue, I collected several reviews and research articles contributed by the experts in the area of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, new and emerging drug targets, natural products, and structure-activity relationships. This issue begins with a research article on “In Vitro and In Silico Studies of Glycyrrhetinic acid derivatives as Anti-Filarial Agents” by Rekha Tyagi and Santosh Kumar Srivastava, reporting antifilarial activity in glycyrrhetinic acid (GA) derivatives. These derivatives reduced the motility of Brugia malayi adult worms by up to 74% while the GA and DEC reduced only up to 49%. Further, GA and most of its derivatives exhibited two times more reduction in the MTT assay when compared to the standard drug DEC. These derivatives also showed 100% reduction of microfilariae and good interactions with Bm-TPP protein. These results may be of great help in developing QSAR model for optimizing a new class of antifilarial lead from a very common, inexpensive, and non toxic natural product [1]. Peroxides are widely used in various areas of life. The rapid development of medicinal chemistry of organic peroxides began in 1971 and is associated with the discovery of antimalarial drug, artemisinin. The second article of this issue is a review article on “Bioactive natural and synthetic peroxides for the treatment of helminth and protozoan pathogens: synthesis and properties” by Prof. Alexander O. Terent’ev and his group. The review is focused on structures and synthesis of peroxides active against parasites causing neglected tropical diseases and toxoplasmosis, describing promising active natural, semi-synthetic and synthetic peroxides compounds found till date [2]. The third article of this issue is also a review on “Strategies to Control Human Lymphatic Filarial Infection: Tweaking Host’s Immune System” by Dr. Puvvada Kalpana Murthy. The review is focused on the advances made in this area such as enhancing the immune competence of host by immunomodulation, combining immunomodulation with antifilarials, identifying immunoprophylactic parasite molecules (vaccine candidates) and identifying parasite molecules that can be potential drug targets [3]. Schistosomiasis is a neglected disease which affects millions of people in developing countries. Its treatment relies on a single therapeutic alternative, praziquantel. This situation may lead to drug resistance; hence there is urgent need for the search of new antischistosomal agents. The fourth article of this issue is a research article on “Vanillin-Related N-Acylhydrazones: Synthesis, Antischistosomal Properties and Target Fishing Studies” by Prof. Josué de Moraes and his group reporting good antischistosomal activity (47.91 μM) for the N-acylhydrazone compound GPQF-407. Further, confocal laser scanning microscopy revealed that it triggered severe tegumental destruction and tubercle disintegration. Target fishing studies pointed out some probable targets, such as the serine-threonine kinases, dihydroorotate dehydrogenases and carbonic anhydrase II. The GPQF-407 can be easily synthesized on large scale from commercially available materials [4]. The fifth article of this issue is a research article on “In Vitro and In Vivo Antifilarial Activity of Standardized Extract of Calotropis procera Flowers against Brugia malayi”, by Dr. P. Kaplana Murthy and her group reporting the microfilaricidal and macrofilaricidal activity of ethanolic extract (A001) and hexane fraction (F001) of C. procera flowers in vitro. In animal models, A001 killed ~49-54% adult worms. In M. coucha model F001 killed 12-60% adult worms in a dose (125-500 mg/kg) dependent manner; A001 and F001 suppressed microfilaraemia till days 91 and 35 post initiation of treatment, respectively. HPTLC analysis revealed presence of lupeol (0.61%), β-sitosterol (0.50%) and 1.50% triacontanol (1.50%) in F001. This is the first report on antifilarial efficacy of flowers of C. procera [5]. In order to develop vaccine and specific diagnostic tests, it is important to characterize different stages of the filarial worms. Microfilariae (Mf) stage of the roundworm is found in host blood or lymph vessels and can be important not only for developing better immunodiagnostics but also for understanding immune recognition and its relevance to immune-pathogenesis and protective immunity. The sixth article of this issue is also a research article on “Immunochemical Characterization of Setaria cervi Microfilarial Antigens using novel antibodies” by Dr. Anuradha Kalani and her group. They prepared four different immune sera against Setaria cervi; intact live, intact live with adjuvant, intact glutaraldehyde fixed with adjuvant and total somatic Mf and used for the immunocharacterization of Mf antigens. The study revealed that compared to fixed intact Mf, live intact Mf were more immunogenic, as the immune sera generated against intact live Mf showed high ELISA reactivity with Setaria cervi Mf and adult worm antigens. All the four immune sera IgG fractions had surface specificity as determined through considerable ELISA reactivity with S. cervi intact Mf. When tested under native conditions (immunoelectrophoresis and crossed immunoelectrophoresis), all the four immune rabbit sera were able to detect antigens of S. cervi Mf and adult stages. These results can be useful in detail understanding of the complex nature of the Mf and adult antigens, which are prerequisite in the development of vaccine and more specific diagnostic tests [6].

Drugs play an important role in treating life-threatening diseases. In most cases these drugs act as inhibitors, as well as enhancers for a certain protein. The protein often participates in metabolic pathways of functional importance and acts abnormally in a diseased state. Interaction of the protein with a drug results in protein function alteration. This concept is used in computational studies to put forward novel compounds having the potential to tackle human diseases. The validation of such compounds require biological testing methods. Computational techniques make use of molecular docking, virtual Screening, interaction mapping, pharmacokinetic and toxicity studies to find the novel compounds [1-7]. Molecular docking requires all the existing inhibitors for the target protein used in the clinical treatment. The inhibitors are made to interact with a specific protein cavity to report a single inhibitor having most stable affinity with it. The single inhibitor is used as a subject for virtual screening which makes a structure-similarity search with a database to yield a huge set of similar compounds. These compounds are again docked with the same protein to finally give an inhibitor showing highest affinity. The selected inhibitor is evaluated using interaction-mapping, pharmacokinetic and toxicity profiling [8-14]. The parameters for interaction-mapping includes H-bond, Van der Waals and electrostatic interactions, and bonded amino acids. Pharmacokinetic and toxicity profiling are evaluated using statistical standards obtained from wet lab studies [15-23]. When the compound passes the final stage of computational validation it is being considered as a novel starting point for further analysis. However, it requires further biological testing methods to proceed further for clinical trials in human diseases. One such method includes the testing of potential novel compound using human cell lines which not only predicts the clinical response but also provide pharmacogenomics hypothesis [24-28]. The compound can also be used in Cancer Stem Cells (CSC) which are usually resistant to drugs [29-35]. Drug identity is achieved using High Performance Liquid Chromatography (HPLC); which also monitors disease therapy progress [36-42]. NMR is a useful tool which has the capability to provide intricate details of target-ligand complex [43-45]. For such drug studies molecule-specific measurements can also be done with high sensitivity using light microscopy techniques (fluorescence coupled with electronic imaging) in living cells [45-49]. Applying such wet lab techniques on the potential compound might give crucial results. Through computational studies, novel compounds for human disease treatment have been mentioned in the recent literature. The compound having Pubchem ID: 44815014 is reported for treatment in osteosarcoma [9]. Similarly, compound SCHEMBL 2031679 (ID: 67254402) and compound CACPD2011a-0001278239 are shown to be effective in chronic myeloid leukemia and bronchial asthma, respectively [10, 11]. The productivity of identifying small molecules have high potential as it produces a lot of data and hope for the treatment of lethal human diseases. 1. 5-Nitrothiophene-thiosemicarbazone derivativess present antitumor activity mediated by apoptosis and DNA intercalation Marques et al. in the current study present an example to determine the activity of N-substituted 2-(5- nitrothiophene)thiosemicarbazone derivatives (LNN-01 to LNN-09) which exhibit valuable antiproliferative activity against several cancer cell lines. In vitro mechanism of action studies revealed that LNN-05 was able to depolarize (dose dependently) the mitochondrial membrane, induce G1 phase cell cycle arrest, and promote morphological cell changes associated with apoptosis in chronic human myelocytic leukemia (K-562) cells. The study highlights 5-(nitrothiophene)thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further study to provide new anticancer therapies [50]. 2. Identification of essential 2D and 3D chemical features for discovery of the novel tubulin polymerization inhibitors Tubulin polymerization inhibitors hinder with microtubule assembly and their functions leading to mitotic arrest, presenting a fascinating target for design and development of novel anticancer compounds. Azimi et al. identify novel tubulin polymerization inhibitors. A combined computational approach was employed to extract the essential 2D and 3D features required for higher activity to identify new anti-tubulin agents. Hypol, Generated model AHHHR, Fischer’s randomization test and the Bayesian models were used to identifying effective 2D-substructures which have incremental or detrimental effects on activity. This developed computational platform provided a better understanding of structural requirements for colchicine site inhibitors for the future investigation. The results of this study will be advantageous for the rational design and optimization of new inhibitors [51]. antitumor agents The cyclooxygenase-2 (COX-2) is known to be over-expressed in several types of human cancer and will be useful tool for cancer chemotherapy. Tugcu et al. in this study focused on determining COX2 inhibitor using quantitative structure activity relationship (QSAR) study on a set of coumarin derivatives using a set of molecular descriptors. A linear model used to predict the growth inhibition on leukemia CCRF cell lines was developed. This brings efficient structural insight in designing novel antitumor COX-2 inhibitors among 86 compounds which were found to be promising inhibitor for leukemia cell. This study, was an integrated approach for repurposing both the biological activity similarity (COX-2 and tumor growth inhibition) and the molecular similarity (chemical class and similarity in molecular descriptors) with computational method approach. This developed model is expected to be effective for estimating inhibitory activity of coumarin derivatives on leukemia cell lines during early drug design [52]. 4. Computer aided - drug design for pharmacological inhibition of ALK inhibitors induces apoptosis and differentiation in Acute Myeloid Leukemia Involvement of mutated Anaplastic Lymphoma Kinase (ALK) positive fusion protein in progression of NSCLC has made a propitious target to inhibit and treat NSCLC. Saphy Sharda describes a paradigm using in silco approaches including molecular docking, structure base virtual screening and various pharmacophore analysis techniques to identify a novel high affinity inhibitor (PubChem CID- 123449015) towards ALK protein which triggers NSCLC. This research has advanced our knowledge of ALK protein and lung cancer which is common among all the cancers worldwide with 1.8 million people diagnosed every year, leading to 1.6 million deaths every year. This research will open up new horizons to deliberate further using in vivo and in vitro analyses [53]. 5. Griseofulvin derivatives: Synthesis, molecular docking and biological evaluation The rapid increase in fungal infections contributes to high mortality rates and has become a major concern. The natural product griseofulvin, (2S,6′R)-7-chloro-4,6-dimethoxybenzofuran-3-one-2-spiro-1′-(2′-methoxy-6-methylcyclohex-2′-en-4-one) is a metabolic product of Penicillium griseofulvum, was one of the first antifungal natural products found in filamentous fungi. Victor Kartsev et al. describe 42 newly synthesized griseofulvin derivatives that exhibit very good antifungal activity against eight fungi tested using various experimentation and in silco approaches including multi component condensation, antifungal and docking studies. Docking analysis to tubulin indicated that compounds behave like griseofulvin. Molecular docking studies revealed that the most active compounds have the same hydrophobic and H-bonding interactions with Thr276 residue observed for griseofulvin, forming 3 hydrogen bonds while griseofulvin only one. The leads obtained from this research may give a positive response on subjecting them to clinical trials [54]. 6. Forging new scaffolds from old: Combining scaffold hopping and hierarchical virtual screening for identifying novel Bcl-2 inhibitors In this study, the authors Kanakaveti et al. focus primarily on refining the chemical space for structurally and functionally employed combos of lead hopping and hierarchical virtual screening. This study assesses the hybrid method for its efficacy in identifying active lead molecules for emerging protein-protein interaction (PPI) targets using virtual screening for a key PPI involved in anti-apoptotic Bcl-2 and its counter pro-apoptotic The results focused on generation of library compounds towards the Bcl2 interface. This research is a novel attempt in terms of activity and binding energy. The extended scaffold hopping approach will accomplish various goals of PPI targets by providing potent leads to modern medicinal chemistry in the future [55]. 7. Identification of high affinity small molecules targeting gamma secretase for the treatment of Alzheimer’s disease Alzheimer’s disease (AD) is a neurodegenerative disease characterized by short term memory loss, behavioral disturbances and interferes with the ability to carry out day to day tasks as the disease progresses in the elderly population. AD is the most common cause of dementia worldwide. The authors Ali et al. in this study emphasize the inhibition of amyloid plaques by blocking the action of gamma secretase protein with inhibitors (GSIs) which forms amyloid-beta (Aβ42) resulting from the sequential cleavage of amyloid precursor protein (APP) by beta and gamma secretases. This research compiles information on gamma secretase inhibitors (GSI) for future research. It provides a new horizon in Alzheimer’s disease research, to be investigated and deliberated further to avert the formation of amyloid plaques [56].

Epigenetic regulation is a reversible process, which is essential for maintaining normal function. Abnormal epigenetic regulation is closely associated with the formation of various diseases including cancer, diabetes, inflammation and neuropsychiatric disorders. Therefore, targeting epigenetic regulation has becoming an emerging strategy for the treatment of diseases, numerous small-molecule compounds are currently being used in clinic or being evaluated in clinical trials. Till date, there are two common epigenetic approaches used for drug discovery: (1) Remodeling the chromatin and affecting global gene regulation by targeting the enzymes responsible for altering the epigenetic code; (2) Targeting the abnormally regulated genes. In this special issue, we aim to provide an up-to-date summary on some epigenetic targets (e.g. HDAC, Sirt2, etc.) and development of related inhibitors for cancer therapy. Duan et al. highlights the promises of epi-drugs to cure cancer and other genetic diseases/disorders [1]. Bai et al. summarize research advances of histone deacetylase inhibitors for epigenetic targeting of cancer [2]. Peng et al. extensively summarize representative HDAC inhibitors and their synthetic routes [3]. Lu et al. highlight recent advances of dual HDAC/PARP inhibitor and their therapeutic potential for the treatment of tumors [4]. Wang et al. show the discovery of Sirt2 inhibitors and highlight their anticancer potential for various cancers [5]. Yin et al. show recent advances and promises of pharmaceutical inhibition of neddylation pathway for various cancers [6]. I am grateful to all the researchers that contributed to this special issue and the referees for their insightful comments.

The series of special issues “New experimental and computational tools for drug discovery” is being published by our journal as a tool to bring together in the same melting pot researchers from many diverse areas that use or develop enabling techniques for Medicinal Chemistry. As consequence, the different issues of this series have merged both experimental and computational areas of research such as Computational Chemistry, Bioinformatics, OMICS, Combinatorial Chemistry, Data Analysis, etc. with applications in Medicinal Chemistry and Drug Discovery. These areas include both experimental techniques (LC-MS/MS, FTIR, or NMR, etc.) combined or not with computational methods like Molecular Docking and Machine Learning (ML), etc. The series have published a total of six special issues until this moment (1-6). The papers included in this number follow the same line and can be summarized as follows: Scotti et al. focused on Hepatitis C research. Hepatitis C is a disease that constitutes a serious global health problem. The aim of this study was combining structure-based and ligand-based virtual screening (VS) techniques to select potentially active molecules against four HCV target proteins from an in-house secondary metabolite dataset (SistematX). From the ChEMBL database, the authors selected four sets of 1199, 355, 290 and 237 chemical structures with inhibitory activity against different targets of HCV to create random forest models with an accuracy value higher than 82% for crossvalidation and test sets. Afterward, a ligand-based virtual screen of the entire 1848 secondary metabolite database stored in SistematX (sistematx.ufpb.br) was performed. In addition, a structure-based virtual screening was also performed for the same set of secondary metabolites using molecular docking. Finally, using a consensus analysis approach combining ligand-based and structure-based VS, three alkaloids were selected as potential anti-HCV compounds [1]. Durruthy et al. focused their work on PIM-1, a kinase related to the oncogenic processes like cell survival, proliferation and multidrug resistance (MDR). In the present work, they tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as daunorubicin (DNR) and vincristine (VCR). In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line. Furthermore, they performed a molecular docking simulation to delve into the molecular mechanism of PIM-1. These results could have a pre-clinical relevance potential in the rational poly-pharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy [2]. Arrau et al. focused on Quillaja saponaria, which contains a high concentration of triterpene saponins that have been used for centuries as a cleansing, antiinflammatory and analgesic agents in Chilean folk medicine. In earlier studies they demonstrated, in mice, both the anti-inflammatory as well as the antinociceptive effect of the major sapogenin, quillaic acid (QA). The objective of this work was to determine the antihyperalgesic effect of QA one and seven days after IP administration of complete Freund's adjuvant (CFA) in male mice using the hot plate test in the presence of complete Freund's adjuvant (HP/CFA) as an acute and chronic skeletal muscle pain model. The present study evaluated the antihyperalgesic activity of QA against acute and chronic skeletal muscle pain models in mice. The authors concluded that QA elicit dose-dependent antihyperalgesic effects against acute and chronic skeletal muscle pain, but QA is more potent than a reference drug in the early and late periods of inflammatory pain induced by CFA [3]. Tenorio et al. pointed out the harmful nature of dioxin in human health and in the whole environment. It is well known among scientists that 2, 3, 7, 8-tetrachloro dibenzo-p-dioxin (TCDD) is an environmental pollutant that causes endocrine disruption, which causes male reproductive toxicity. The objective of the present study was to evaluate the toxicity of low doses of TCDD in male CD1 mice. The results show that the body weight of the treated animals was reduced in medium and high doses (0.75, 1.5 mg / kg) with respect to the control groups. In the groups treated with TCDD, the abnormal sperm increased by 52.5% more than the control group. Significant differences in apoptosis were observed between the negative control and vehicle control, including at the median dose (0.75 mg / kg). It was concluded that at these low doses there was an impact on the quality of the mouse sperm, and an effect on apoptosis and cytotoxicity of sperm exposed to these doses of TCDD [4]. Marrero-Ponce et al. extended previously defined Graph Derivative Indices (GDIs) introducing the concepts of Higher Order Derivatives and Mixed Derivatives. The result of applying the higher order and mixed GDIs over any molecular structure allow finding Local Vertex Invariants (LOVIs) for atom-pairs, for atoms-pairs-pairs and so on. All new families of GDIs are implemented in computational software named DIVATI (acronym for Discrete DeriVAtive Type Indices), a module of the TOMOCOMD-CARDD program (KeysFinder Framework). QSAR modeling of the biological activity (Log 1/K) of 31 steroids reveals that the GDIs obtained using higher order and mixed GDIs approaches yield slightly higher performance compare to previous reported approaches based on the duplex, triplex and quadruplex matrix. The higher order and mixed GDI method, appear as a promissing tool in QSAR/QSPRs, similarity/dissimilarity analysis and virtual screening studies [5]. Pérez-Castillo et al. developed computational models for the identification of antimalaric hit compounds. For this, a data set suitable for the modeling of the anti-malaria activity of chemical compounds was compiled from the literature and subject to a thorough curation process. In addition, the performance of a diverse set of ensemble-based classification methodologies was evaluated and one of these ensembles was selected as the most suitable for the identification of antimalaria hits based on its virtual screening performance. During the compilation of the data set it was possible to obtain high quality data which was curated to ensure that the noise was as low as possible in the modeling process. Among the explored ensemble based methods, the one combining Genetic Algorithms for the selection of the base classifiers and Majority Vote for their aggregation showed the best performance. The results also show that ensemble modeling is an effective strategy for the QSAR modeling of highly heterogeneous datasets in the discovery of potential anti-malarial compounds [6].

Chemotherapeutic agents have saved millions of lives from many deadly diseases as well as transformed the pharmaceutical industry. In the progress of technology and therapeutics, human civilizations are facing the troublesome situations due to drug resistant transporters. In this thematic issue, I collected several manuscripts contributed by experts in the field of drug resistance/molecular biology of transporters/medicinal chemistry of botanicals. Transporters are considered as key factors for the multidrug resistance (MDR) mechanism that extrudes unrelated drugs/compounds from the cytoplasm of cells. To combat this problem, research has been focused now on the development of synergistic combinations against these drug transporters which are now potential therapeutic targets. I now turn to the content of this issue which provides the up-to-date summary on botanicals/endophytic compounds and their role in modulation of multidrug transporters. The first manuscript summarized the therapeutic potential of endophytic compounds. This study focused on the drug transporters, mutualistic chemical diversity, exploring novel chemical matter and drug transporter modulating potential of endophytes [1]. The second manuscript summarizes the magical medicinal importance of the Ammannia spp.; their use in folklore remedy, herbal formulations, biological activities of extracts, isolation of bioactive phytomolecules and an SAR study of semi-synthetic derivatives to analyze the possibility of new drug molecule(s)/drug modulators of plant origin [2]. The third manuscript emphasizes the role of ATP-binding cassette (ABC) transporters in neurodegenerative diseases and significance of botanicals as modulators of ABC transporters [3]. The fourth manuscript provides the up-to-date summary on antifungals from plant and marine sources which can be realized by combinatorial studies along with standard anti-fungals [4]. The fifth manuscript describes the recent advancements and historical developments observed during the past 42 years (1976-2018) focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes (ozonides) [5]. The sixth review encompasses the most important secondary metabolites of plants i.e. glycosides (niazirin and niaziridin) as drug resistance reversal agent acting through efflux pump inhibition and modulation of expression pattern of drug resistance genes which may help in developing an effective antibacterial combination from glycosides [6]. The seventh manuscript reviews the important molecular targets such as parasite transporters, membrane biosynthesis, mitochondrial system, apicoplasts, the shikimate pathway, hematin crystals, parasite proteases, glycolysis, isoprenoid synthesis, cell cycle control/cyclin-dependent kinase, redox system, nucleic acid metabolism, methionine cycle and the polyamines, folate metabolism, the helicases, erythrocyte G protein, and farnesyl transferases to develop novel antimalarials through modern genomic tools approaches. The last review encompasses the development of resistance by carbapenemase and drug transporters as important targets for pharmacokinetic studies [7]. This review also explores wide variety of botanicals as their probable inhibitors [8]. Last but not the least our sincere gratitude for the support by all who were directly or indirectly helped us to make this issue a success. We specially thank Dr. Allen B. Reitz (Editor-in-Chief), Ambreen Irshad (Senior Editor), Maria Khan (Editorial Manager). We owe utmost gratitude towards referees and the authors. Without their help, we could not have such a good thematic issue.

Tuberculosis (TB) is one of the top 10 causes of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. Further, development of resistance against the frontline anti-tubercular drugs has worsened the already alarming situation. In 2017, 558 000 people (range, 483 000–639 000) developed TB that was resistant to rifampicin (RR-TB), the most effective first line drug, and of these, 82% had Multidrug-Resistant TB (MDR-TB). The four inexpensive and effective first lines anti TB drugs (ethambutol, isoniazid, rifampicin and pyrazinamide) were established nearly fifty years ago. Although during this period many active compounds underwent clinical trials, but none of them could get US-FDA approval. After a gap of more than 40 years or so, recently in December 2012, USFDA accorded approval to the first drug “bedaquiline” for MDR-TB patients who are under treatment for 2 years or so. Therefore, there is an urgent need of intensive drug discovery to develop new, more effective, affordable and accessible anti-tubercular agents possessing novel modes of action, which could reduce the time and burden of all kind of drug resistant TB. In order to control tuberculosis, there is a urgent need to develop novel and more efficient drugs. In this context, targeting the pathogen virulence factors, and particularly signal mechanisms, seems to be a promising approach. An important transmembrane signaling system in Mtb is represented by receptor-type Serine/Threonine Protein Kinases (STPKs). Mtb has 11 different STPKs, two of them, PknA and PknB, are essential. By contrast PknG and PknH are involved in Mtb virulence and adaptation, and are fundamental for the pathogen growth in infection models. Therefore, STPKs represent a very interesting group of pharmacological targets in M. tuberculosis. In this review Prof. Chiarelli has presented and discussed the principal inhibitors of the mycobacterial STPKs. In particular, medicinal chemistry efforts have been focused on discovering new antimycobacterial compounds, targeting three of these kinases, namely PknA, PknB and PknG demonstrating that targeting Mtb STPKs could be a new promising strategy for the development of drugs to treat TB infections [1]. Hispolons are natural products and recently anti TB activity in these compounds have been reported. In this research article Prof. Muthyala Murali Krishna Kumar and his co-workers tried to optimize the structure with bioisosteric replacement of 1,3- diketo functional group with the corresponding pyrazole and isoxazole moieties. They prepared a total of 44 compounds and screened for anti TB activity and antibacterial activity. Among all two compounds showed highest potency with MIC 1.6μg/mL against M. tuberculosis H37Rv. Further, they concluded that computational studies and in vitro screening results are indicating at mtFabH as the probable target for these compounds [2]. Some time ago Prof. Marcus Vinícius Nora de Souza described a new class of active mefloquine derivatives against sensitive and resistant strains of Mtb. In this research article he and his group members synthesized a series of new 2,8- bis(trifluoromethyl)quinoline derivatives and evaluated for their in vitro antibacterial activity against sensitive Mycobacterium tuberculosis ATCC 27294 and resistant strain SR 2571/0215 (resistant to Rifampicin and Isoniazid). Among all, three compounds showed the highest activity. All compounds were tested against three cancer cell lines and showed low cytotoxicity. Among the three one compound was the most potent against resistant and sensitive Mycobacterium tuberculosis in this series with important information and perspectives in the search of new bioactive compounds based on Mefloquine analogs [3].

Tuberculosis (TB) is one of the top 10 causes of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. Further, development of resistance against the frontline anti-tubercular drugs has worsened the already alarming situation. In 2017, 558000 people (range, 483000-639000) developed TB that was resistant to rifampicin (RR-TB), the most effective first line drug, and of these, 82% had Multidrug-resistant TB (MDR-TB). The four inexpensive and effective first lines anti TB drugs (ethambutol, isoniazid, rifampicin and pyrazinamide) were established nearly fifty years ago. Although during this period many active compounds underwent clinical trials, but none of them could get US-FDA approval. After a gap of more than 40 years or so, recently in December 2012, USFDA accorded approval to the first drug “bedaquiline” for MDR-TB patients who are under treatment for 2 years or so. Therefore, there is an urgent need of intensive drug discovery to develop new, more effective, affordable and accessible anti-tubercular agents possessing novel modes of action, which could reduce the time and burden of drug resistant TB. The recent years have witnessed 4H-1,3-benzothiazin-4-one as a promising class of antimycobacterial agents specially against resistance TB strain. In this regard Prof. de Souza and Nogueira have presented a detailed review discussing the different aspects of this chemical class such as synthesis, mechanism of action, medicinal chemistry and combination with other drugs [1]. DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolones class of antibacterials. But in order to treat serious infections, including multi-drug resistant tuberculosis fluoroquinolones are increasingly being overutilized. This increases the probability of resistance to fluoroquinolones, which is mediated by a single amino acid change in gyrA, leading to class wide resistance. The third article of this issue by Dr. Sidharth Chopra and his group provide an overview on the recent progress in identifying novel scaffolds which target DNA gyrase and provide an update on their discovery and development status [2]. In this thematic issue, I collected several reviews and research articles contributed by the experts in the area of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, new and emerging drug targets, natural products, and structure-activity relationships. This issue begins with a research article on “Dihydroartemisinin and its analogs: A new class of antitubercular agents” by Komal Kalani and Santosh Kumar Srivastava, reporting for the first time anti-tubercular potential of Dihydroartemisinin (DHA) and its derivatives. Further, synergistic activity of a DHA derivative was also carried out with frontline anti-TB drugs, which showed synergistic effect with RFM. Therefore, DHA derivatives have potential for anti-tubercular drug development from an inexpensive and non-toxic natural product [3]. Isocitrate lyase (MtbICL), a key enzyme of glyoxylate pathway has been shown to be involved in the persistence, is an attractive drug target against persistent mycobacteria. In this regard, Dr. Ashok Sharma and his group have integrated virtual screening, which resulted in the identification of shinjudilactone (quassinoid), lecheronol A (pimarane) and caniojane (diterpene) as potential MtbICL inhibitors [4]. Tryptanthrin is a known inhibitor of Mtb enoyl-acyl carrier protein reductase (InhA). In this regard, Prof. Macaev and his group members modified the structure of tryptanthrin in such a way that it gave a group of 5H-[1,3,4] thiadiazolo [2,3- b]quinazolin-5-one analogues with varying degree of antimycobacterial activity. The most active compound exhibited superior inhibition activity (up to 100%) against mycobacterial growth at MIC 6.5 μg/mL and demonstrated a very low per oral toxicity in animals. He also carried out molecular modeling studies to investigate the binding mechanisms of the synthesized ligands with InhA [5]. It is known that several imidazole and 1, 2, 4-triazole derivatives possess both antimycobacterial and antifungal activity. Keeping this thing in mind Prof. Daniele Zampieri and his group members synthesized some 1-(1-(aryl)-2-(2, 6-dichlorophenyl) hydrazono)ethyl-1H-imidazole and 1H-1,2,4-triazole derivatives and evaluated their antitubercular activity. Among the series two derivatives showed most promising activity and, according to the docking assessment, the compounds could be CYP51 inhibitors [6]. In an earlier communication Dr. S.K. Srivastava and his group members for the first time reported anti-tubercular activity in dihydroartemisinin (DHA-1) against Mtb H37Rv, which prompted him to carry out chemical transformation of DHA into various derivatives and study their antitubercular potential. Thus, as a part of their drug discovery program in this research article they semi-synthetically converted DHA into four new acyl derivatives and in-vitro evaluated their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. Two out of the four derivatives showed MIC 12.5 and 3.12μg/mL Further, in silico studies of the most active derivative showed interaction with ARG448 and inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages. Finally, this derivative also killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. Since, dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non toxic natural product [7].

Modern drug discovery has now become largely target-based, where attempts are made to find chemical agents that can hit the disease-specific enzymes or pathways. In this context, Protein-Protein Interactions (PPIs) have emerged as an interesting class of targets. Several biological processes, such as cell growth, DNA replication, transcriptional activation, transmembrane signal transduction, etc., are regulated by multiprotein complexes whose activity and specificity are controlled by proteinprotein interactions. Thus two issues of this journal have been devoted to highlighting the roles of PPIs. While the previous issue (Part I) has covered several issues of PPIs such as ‘How Cancer Cells Resist Chemotherapy’, ‘Nanoparticles as Carriers for Drugs Targeting Protein-Protein Interactions’, ‘PPI-based Design of Kinase Inhibitors’, etc., this second part has highlighted other roles of PPIs. First, article here is entitled ‘Protein-Protein Interaction and Aggregation Inhibitors in Alzheimer’s Disease’ and has been written by Ganeshpurkar et al. It presents an update on design and development of drugs based on protein- protein interactions for the treatment of Alzheimer’s Disease (AD), a multifaceted disorder, involving complex pathophysiology and a plethora of protein-protein interactions [1]. In second article, Cicaloni et al. have presented in detail the applications of in silico methods for design and development of drugs targeting protein-protein interactions. Several approaches, models and methods from graph theory are applied to PPIs in order to reveal hidden properties and features of an intricate network of proteins. Network profiling together with the extraction of knowledge is crucial to better understand the biological significance of PPIs [2]. In third article entitled ‘Protein-Protein Interactions of Phosphodiesterases’, Al-Nema and Gaurav highlighted some of the general characteristics of phosphodiesterases (PDEs) and focused mainly on the protein-protein interactions of selected PDE enzymes. PDEs are proteins which do not operate alone but in complexes made up of a large number of proteins which bind to each other via protein-protein interactions [3]. These three articles have highlighted the roles of PPIs in drug development and might be of great interest to those involved in biochemical and pharmaceutical research. I have equally enjoyed reading these three articles too and hope so will also the readers.

Modern drug discovery has now become largely target-based, where attempts are made to find chemical agents that can hit the disease-specific enzymes or pathways. In this context, protein-protein interactions (PPIs) have emerged an interesting class of targets. Several biological processes, such as cell growth, DNA replication, transcriptional activation, transmembrane signal transduction, etc., are regulated by multiprotein complexes whose activity and specificity are controlled by protein-protein interactions. It has been now well understood that various human diseases are associated with aberrant protein-protein interactions. Among them the notable ones are cervical cancer, leukemia, bacterial infections, inflammation, diabetes, osteoporosis, and neurodegenerative diseases. Consequently, over the last decades, protein-protein interactions have developed into attractive molecular targets for the discovery of potential drugs. Thus, drug design targeting PPIs is a burning area and the present two thematic issues on it present some very interesting articles covering some important aspects of this area. The very first article in this issue entitled as ‘How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions’ and authored by Tarasov et al. has discussed the feasibility of predicting general and specific resistance mechanisms to chemotherapy [1]. The second article authored by ‘Athanasios et al. on ‘Algorithmic and Stochastic Representations of Gene Regulatory Networks and Protein-Protein Interactions’ presents properties and representations of PPIs and gene regulatory networks that can be used for the early diagnosis of diseases [2]. In article 3 entitled as ‘Quantum Molecular Dynamics, Topological, Group Theoretical and Graph Theoretical Studies of Protein-Protein Interactions’ Balakrishnan and Gupta have reviewed some theoretical studies on PPIs involving hybrid quantum molecular dynamics, quantum chemical, topological, group theoretical, graph theoretical, and docking studies and discuss how these theoretical studies facilitate the discovery of PPI inhibitors of therapeutic importance [3]. In article 4 entitled as ‘Protein/Hormone Based Nanoparticles as Carriers for Drugs Targeting Protein-Protein Interactions’, authors Al-Suhaimi et al. discuss the use of protein- based nanoparticles as carriers for drugs targeting protein-protein interactions and also highlight the use of protein hormone- based nanoscale in health and disease. Protein-protein interactions are of crucial importance in regulating the biological processes of cells, both in normal and diseased conditions. Recently, significant progress has been made in targeting PPIs using small molecules and achieving promising results [4]. In article 5, therefore, which is entitled as ‘Influence of Amino Acid Mutations and Small Molecules for Targeted Inhibition of Proteins Involved in Cancer’, Kanakaveti et al. have focused on the advancements in computational research for targeted inhibition of proteins involved in cancer. Kinases are key modulators in regulating diverse range of cellular activities and are an essential part of the protein-protein interactome [5]. The last article ‘Targeting Kinase Interaction Networks: A New Paradigm in PPI-based Design of Kinase Inhibitors’ authored by Jenardhanan et al. presents briefly the structure and function of few important kinases and highlights the protein-protein interaction (PPI) mechanism of kinases and the kinase specific interactome databases [6]. I have greatly enjoyed reading all these articles and hope so will do the readers and find them useful for further research on protein-protein interactions.

This issue is related to current trends in enzyme inhibition and activation in drug design. The topics which are presented deal with prediction of drug-drug interactions, as well as enzymes involved in tuberculosis, IMPDH enzymes, antimicrobial activity of thiazole-based chalcones and PTP1B inhibitory action and anti-diabetic properties. The first paper deals with prediction of drug-drug interactions (DDIs) related to inhibition or induction of drug-metabolizing enzymes. There are three types of DDIs: pharmacokinetic (PK), pharmacodynamic, and pharmaceutical. PK is the most frequent type of DDI, and often it appears as a result of inhibition or induction of drug metabolizing enzymes (DMEs). In this review, in silico methods that may be applied for prediction of inhibition or induction of DMEs are summarized and appropriate computational methods are described for DDI prediction, showing the current place and perspectives of these approaches in medicinal and pharmaceutical chemistry. Sources of information on DDIs that can be used in pharmaceutical investigations, medicinal practice and computational models creation are explained in detail and the problem of inaccuracy and redundancy of this data is discussed. The methods of computer-aided prediction of DDI including the state-of-the-art in physiologically based pharmacokinetic (PBPK) computational approaches and in protein-based in silico methods dealing with DMEs is provided. In the section of ligand-based methods is described utilization of pharmacophore models, molecular field analysis, quantitative structure-activity relationships (QSAR), and similarity analysis applied to prediction of DDIs related to inhibition or induction of DMEs. Also the problem of DDI severity assessment is addressed highlighting the issues, perspectives and practical use of in silico methods is discussed [1]. The next paper deals with Mycobacterial tuberculosis enzymes. A literature search has been carried out to find the different chemical molecules including drugs and their enzyme targets responsible for their antitubercular activities in recent years. This review provides an overview of the chemical structures with their antitubercular activities and enzyme targets like InhA, ATP synthase, Lip Y, transmembrane transport protein large (MmpL3), decaprenylphospho-β-D-ribofuranose 2-oxidase, (DprE1). The major focus has been on the new target ATP synthase. Such an attempt may be useful in designing of new screening using the Asinex database considering the important three sub-structures of bedaquiline (TMC 207) containing quinoline, tertiary amine and hydroxyl functionality identifying amodiaquin to have these features but with no antitubercular activity. These studies were followed by molecular docking using a homology model of mycobacterial ATP synthase and a set of 18 novel substituted chloroquinolines, belonging to the 2-methyl-4-substituted amino-7-chloroquinolines. This compound library was designed , synthesized and screened against Mycobacterium smegmatis ATP synthase; 6 compounds (4-9) with the lowest inhibitory concentration (IC50) values (0.36–1.83 μM) were selected for further in vitro studies. A variety of different compounds such as benzo[d]oxazol-2(3h)-ones derivatives, pyrrolidinone and pyrrolidines, tetrahydropyrans, methylthiazoles and many others were synthesized and evaluated against InhA, enzymes involved in the synthesis of mycobacterial cell walls [2]. Another paper is dedicated to design, synthesis, evaluation of antimicrobial activity and molecular docking study of new thiazole-based chalcones. The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. Compounds were tested also against three resistant strains (MRSA, P. aeruginosa and E. coli). All 28 tested compounds were active showing in some cases better activity than ampicillin and streptomycin, and all compounds were much more potent than ketoconazole and bifonazole [3]. Docking studies indicated that DNA gyrase, GyrB and MurA inhibition may explain antibacterial activity, while 14- alanosterol demethylase of CYP51 may explain the antifungal activity. Another interesting target is Helicobacter pylori IMPDH. Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population. Taking into account increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Thus, fourteen aryldiazenyl substituted indoles were synthesized and evaluated against IMPDH. Several lead molecules which could help in a further endeavor toward identifying selective and potent inhibitors of the Hp IMPDH to fight multi-drug resistance in H. pylori infections were identified [4]. The last paper is dealing with docking assisted prediction and biological evaluation of Sideritis L. components with PTP1B inhibitory action and probable anti-diabetic properties. Sideritis L. (Lamiaceae) is a herbal plant growing around the Mediterranean sea which has been included in the Mediterranean diet for centuries. The antioxidant and anti-inflammatory activity of the components of Sideritis L. were evaluated previously and the aim of this paper was to investigate the potential of some sideritis’s components to act as PTP1B inhibitors, thus exhibiting beneficial effect in the treatment of diabetes II. Docking prediction was performed and the components of Sideritis L. were evaluated for their PTP1B inhibitory activity. Four of the five tested components exhibited inhibitory action. Both an acetoside and lavandulfolioside showed the best activity with IC50 values of 4.0 μΜ and 9.3 μΜ with competitive and uncompetitive modes of inhibition, respectively [5].

This issue is related to current trends in enzyme inhibition and activation in drug design. The topics which are presented deal with inhibitors of PTP1B, PDE5A, Alzheimer disease, xenobiotic metabolizing enzymes as well as caffeic acid derivatives as antimicrobial agents. The first paper show the attempts made in developing of Protein Tyrosine Phosphatase (PTP1B) inhibitors with high potency, selectivity and bioavailability and sum up the indications for favorable structural characteristics of effective PTP1B inhibitors. The research for finding PTP1B inhibitors started with the design of molecules mimicking the tyrosine substrate of the enzyme and revealed the main requirements for small inhibitors binding to the active site surrounding Cys215. Permanent inhibition of the enzyme by oxidation of the catalytic Cys215 is also highlighted. Moreover, covalent modification of Cys121, placed near but not inside the catalytic pocket, has been associated with permanent inhibition of the enzyme [1]. The next review refers to the Acetylcholinesterase Enzyme (AChE), which is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD, but these drugs provide only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time. The review focused on the development of different strategies targeting the AChE enzyme along with other targets like Butyl Cholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals antioxidant properties and free radical scavenging capacity. Topics covered include the cholinergic hypothesis, selectivity for AChE over BChE, classification of AChE inhibitors and hybrid strategies. Several hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates, and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule. This is followed by optimization of the activity through structural modifications guided by structure activity relationship studies, leading to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity against other above-mentioned targets for further pre-clinical studies [2]. The next review on xenobiotic metabolizing enzymes may find useful applications in related medical interventions or help in the development of more efficient drugs since xenobiotic metabolizing enzymes are important for the metabolism, elimination and detoxification of exogenous agents, and are found in most tissues and organs. These are distinguished into phase I and phase II enzymes, as well as phase III transporters. An extensive review on several aspects of metabolism such as effect of reoxygenation, stress, resistance to drugs and drug metabolism, restoration of impaired drug metabolism in adjuvant-induced disease, effect of spironolactone or phenobarbital on cholesterol organ concentrations, interaction of some H1 and H2 receptor antagonists with cytochrome p450, interaction of ethanol with drugs-involvement of CYPs, induction of CYP4a and peroxisomal β-oxidation, carbonyl reduction and drug metabolism and effect of selected natural and synthetic compounds on drug metabolism are presented [3]. The next paper refers to antimicrobial activity of caffeic acid derivatives, selected based on computer-aided predictions. Twelve tested compounds have shown good antibacterial activity. Five out of twelve tested compounds appeared to be more active than the reference drugs ampicillin and streptomycin. Despite that all compounds exhibited good activity against all bacteria tested, the sensitivity of bacteria towards compounds in general was different. The evaluation of antifungal activity revealed that all compounds were more active than ketoconazole, while seven compounds (2, 3, 4, 5, 7, 8 and 12) appeared to be more active than bifonazole. Docking results indicate that gyrase inhibition is the putative mechanism of antibacterial action while the inhibition of 14α-demethylase may be responsible for antifungal action. Prediction of cytotoxicity by PROTOX showed that compounds are not predicted to be toxic (LD50 1000-2000 mg/kg) [4]. Another inhibitor that are presented in this issue is PDE5A a phosphodiesterase which specifically hydrolyzes the cGMP to GMP. A simple but efficient route for the synthesis of novel 8–morpholino-2-aryl–2, 5-dihydro-3H-pyrazolo[4, 3-c]quinoline- 3-one derivatives is reported. Molecular docking studies of synthesized compounds with human PDE5A protein shows that all the compounds exhibited good docking score in comparison with known inhibitors. In addition, all the synthesized molecules were evaluated against HCT116 cell lines for their antitumor activity. Compounds 5a, 5d, and 6e showed better cytotoxicity and can be studied as potential inhibitors of PDE5A [5].

The first part of this issue mainly focuses on medicinal developments driven by functional peptides. This part is the continuation of drug discovery and design, but this time with emphasis on developments driven by functional molecules, especially drugs or their derivatives from natural products. The selected reviews are summarized as follows: As a common mental disorder that mainly occurs in 60 years old or elderly people, Alzheimer’s disease (AD) is a major threat to public health system. In the review regarding AD treatment, Wu et al. comprehensively summarized newly reported natural products with anti-AD activities, including acetylcholine-related natural products, Aβ and tau protein related natural products, antioxidants, anti-inflammatory and other neuroprotective natural products, as well as NMDA receptor antagonists [1]. Although some natural products show promising preliminary results in AD treatment, they are still a long way from clinical transformation. A Chinese scientist Youyou Tu won the 2015 Nobel Prize in Physiology or Medicine because of the outstanding contribution to the discovery of antimalarial drug artemisinin that is extracted from an herbal prescription. Although artemisinin and its derivatives were primarily developed as antimalarial agents, later extensive studies have witnessed other pharmaceutical potentials beyond malaria. Thus, the paper of Liu et al. highlights new pharmaceutical effects of artemisinin derivatives with a focus on the antitumor and antivirus activity [2]. Due to the therapeutic potential of histone deacetylases (HDACs) as one of promising drug targets in cancer, HDAC inhibitors have been intensively investigated over the last few decades. In the last review, Li et al. explored the developed synthetic and natural HDAC inhibitors according to different zinc binding groups (ZBGs) and discussed their binding mode with zinc ion in detail, to point the way forward for the design and development of HDAC inhibitors with novel ZBGs [3]. Finally, we would like to express our sincere gratitude to all authors, reviewers as well as the editorial staff of Current Topics in Medicinal Chemistry for their kind contributions and excellent support to this issue. Haoxing Wu also acknowledges partial financial support from the grant of National Natural Science Foundation of China (Grant No. 21602146).

This editorial provides a brief overview of this thematic issue. The thematic issue is proposed to help medicinal chemists and biologists track the most recent insilico drug discovery research and high-throughput methods in molecular biochemistry. Traditional drug design strategy suffers from long periods of time and the high cost of drug development, which benefits from the recently developed computationbased drug discovery approaches. These approaches include virtual drug screening, molecular dynamics, docking and epitope recognition. The collection of this thematic issue include six articles. The first one reviews the recent advances in in silico B-cell epitope prediction. The second one proposes a novel improved biogeography-based optimization and applies it to plant drug extraction. The third one focus on the proteinprotein interaction network analysis of virulence proteins of Aspergillus fumigatus. The fourth one designs and synthesizes novel MAO inhibitors with antioxidant potential, and evaluates the former as novel multifunctional agents against monoamine oxidase A and B. The fifth article critically reviews the various in silico techniques, including 3D QSAR, COMFA, and molecular docking, for study of the natural product based xanthine oxidase inhibitors. The sixth reviews interactions between resveratrol and various ligands, and studies that focus on resveratrol using molecular docking strategies.

In the past few decades, the upsurge of various deadly diseases that mar our well being and progression is increasing the necessity to develop safe and effective theranostic methods. Peptide-based probes are becoming the “state of the art” in targeted theranostics since they can be conjugated with imaging moieties (e.g. organic dyes, radionuclides, or quantum dots) for targeted diagnosis and be formed into nanoparticles or biocompatible material for targeted therapy. Further, these probes can provide biological information at the molecular level during disease process, which is consistent with the concept of precision medicine. The first part of this present special issue mainly focuses on the recent developments and applications of peptide-based probes in medicinal chemistry, including peptide design based on machine learning, radionuclide-labeled peptides for cancer imaging and therapy, peptide-based nanoparticles, and drug delivery for cancer therapy. Although it represents only a small portion of current research, this issue strives to include several typical and significant topics contributed by extraordinary scholars in frontier research of this field. We sincerely hope that these reviews foster interest and enthusiasm for functional peptides in theranostic applications. The papers included in this part can be summarized as follows: In the opening paper of this issue, Wu et al. systematically introduced machine learning approaches to predict activity of the peptide, especially antimicrobial peptides (AMPs), anticancer peptides (ACPs) and anti-inflammatory peptides (AIPs), including contents of peptide-based bioinformatics resources, general workflow of machine learning, and several predictive tools [1]. Compared to traditional screening techniques, this accurate and effective technique will be of great benefit to the discovery of active peptides. Due to playing important roles in tumor initiation, progression and metastasis processes and over-expression in many solid tumor types, C-X-C chemokine receptor 4 (CXCR4) has become a very important target for cancer imaging and therapy. Liu and co-authors presented the potential of CXCR4-targeted peptides labeled by various radionuclides (such as 111In, 18F, 68Ga and 177Lu) for the targeted theranostics of CXCR4- positive tumors [2]. Although there were some minor flaws in preclinical studies, the promising data certainly promoted the translation of these probes to clinical application. Similarly, prostate-specific membrane antigen (PSMA) is considered a valuable target for both the diagnosis and therapy of prostate cancer. Diao et al. described a comprehensive overview of the PSMA ligand-based agents for radiotheranostic, especially those that have been clinically adopted [3]. For treatment of prostate cancer, Zhang et al. demonstrated another method that is nanoparticle therapy [4]. In their review, different types of therapeutic nanoparticles for prostate cancer, especially those based on targeting receptors such as PSMA or gastrin-releasing peptide (GRP) were described in detail to provide further understandings and recommendations on the design and development of targeted nanoparticles. In addition to targeting cancer cells, specific peptide sequences were also used for the selective identification by a protease when introduced into peptide chains/linkers or polymer-peptide conjugates, which was an essential part of enzyme-responsive drug delivery systems [5]. Our sincere thanks are due to the editorial staff for their great support during the whole process. Haoxing Wu also acknowledges partial financial support from the grant of National Natural Science Foundation of China (Grant No. 21602146).

Burgeoning rise in different disease cases such as cancer, viral diseases including Dengue, Chikungunya, Zika, Ebola, Japanese encephalitis, etc., other tropical and neglected diseases, metabolic conditions such as diabetes and many other health conditions warrants the need of immediate investigations and end the human plight for ensuring a better tomorrow. Advances in scientific research have shown the impact in eradication and prevention of many diseases conditions such as polio. Interplay of experimental and theoretical approaches have come a long way in proving their effectiveness and worth in this regard. Earlier computational approaches were almost ignored by a large section of the scientific community. Last few decades have witnessed a drastic change in the existing beliefs and today theoretical techniques are not only supporting and supplementing experimental results but also guiding studies by providing valuable cues. Computational approaches pertaining to understanding complex biological system have come a long way during past few years rising from its infancy to blooming into a full-fledged science. Simple bioinformatics and chemo-informatics approaches are being frequently applied in the arena of system biology and are providing remarkable insights on unsolved and unanswered scientific questions so far.

Battling diseases requires concerted efforts towards innovation and discovery. In today’s world and time, we face unprecedented challenges of organizing and prioritizing our strategies against diseases. Development of effective and commercially feasible therapeutic agents or drugs is a time consuming and labour–intensive process which thrives on an array of resources. It is assumed that application of Computer Aided Drug Design (CADD) for prospecting and profiling of new lead compounds in initial stages of drug discovery pipeline will offer many advantages both in terms of monetary gain and optimal use of available resources. Computational chemistry, a combinatorial subject has come a long way from its initial days of being considered as an auxiliary science to an indispensable part of most modern drug developmental programs. As the trend shifted from one gene or protein approach towards the whole genome or proteome analysis in unveiling disease mechanism and progression, computational approaches slowly but steadily made their way in domain once owned exclusively by medicinal chemists or biologists. The field has grown by leaps and bounds not only because of advances in computational technology, software development and processing speed but also because of mammoth scale and rapid pace of generation of experimentally derived data and myriad types of data available waiting to be analyzed and used. Computational approaches are touching all realms of life and have catapulted to a position where their crucial role in generating and validating hypotheses, disease identification, knowledge discovery, therapeutics and control by identification of novel drug targets, drug molecules and vaccines cannot be denied. Some of the well known applications of computational approaches in drug designing include structure elucidation by molecular modeling, Quantitative Structure-Activity Relationships (QSAR), docking and molecular simulation, toxicity prediction, machine learning and data mining approaches for data analysis and visualization. Considering the huge risks of reemergence and resurgence of infectious diseases and the problem of drug resistance along with the mounting costs of drug development programs and time gaps, it is only prudent to adopt and integrate computational techniques and programs in drug discovery pipelines to expedite the progress by turning the scale in our favor by cutting down costs of such ventures by shortening the drug discovery cycle and reducing efforts, manpower and time duration. Computational approaches have now become an integral part in storage, management, comparative analysis and in obtaining in-depth knowledge of disease due to their versatility. Computer aided drug design, genomics and proteomics, metabolomics, interactomics play a crucial role in mining hidden molecular information, pattern recognition and finally interpretation of biological significance. Computational chemistry is being widely used at different stages of drug design and production like target identification, target validation, lead identification and lead optimization in the pharmaceutical industry and has emerged as powerful tools complementing traditional chemical screening methodology. A synergistic relation between information technology and routine experimental approaches is required to handle and process voluminous and diverse datasets generated through genomics and high throughput screening methods and increasing the reliability of the outcomes. Incorporation of techniques based on artificial intelligence and use of large scale distributed computing for screening have provided a much needed impetus to drug discovery programs. Considering the array of disciplines and sub-disciplines involved with computational approaches and vast number of diseases we are dealing with, the topic requires series of issues to present the recent advancement and understanding on the subject. Our aim as editors is to bring forth informative articles that highlight the ongoing research in the computational front with respect to various diseases. We received enormous response and witnessed enthusiasm from the researchers to contribute in this series of issues. After successful completion of Part-I (Volume 18, Number 13), here we present the Part II (Volume 18, Number 31) with some selected articles summarizing interesting application of the implementation of computational approaches. The article by Salam et al. focuses on computational structural development and potential inhibitor targeting B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), which are important targets for lymphoma [1]. Kaur and coworkers reviewed the structural insights required for the inhibition of HIV1 integrase [2]. Novel computational analyses for screening Cryptococcus species have been thoroughly outlined by Manjunath and Skariyachan [3]. Bashir and coworkers presented a general and overall perspective on the modern theoretical and computational aspects with respect to human diseases [4]. Kalra and coworkers highlighted the influence of physicochemical properties of functional groups such as ethers and esters at the 10th position of artemisinin derivatives in optimizing the anti-malarial activity [5]. Tiwari and coworkers reported Acetate kinase (AcK) as a broad-spectrum novel target in Mycobacterium tuberculosis, Vibrio cholerae, and pathogenic Escherichia coli [6]. Our sincere thanks are due to Dr. Allen B. Reitz, the Editor-in-Chief of Current Topics in Medicinal Chemistry for providing us this opportunity of bringing forth this special issue. It has been a great team effort. We would like to express our sincere thanks to Ms. Ambreen Irshad, Associate Editor and Maria Khan, Editorial Manager. We are thankful to the Editorial staff for their great support at every step of this issue. We are sincerely grateful to the authors for their contribution and patience during the review process. Contribution of the renowned reviewers deserves special mention; we acknowledge their support and efforts in scrutinizing manuscripts and providing valuable comments and suggestions for improving the quality of manuscripts. We believe that this special issue will be interesting for the readers of the journal.

Development of novel anti-cancer drugs is one of the most important theme in cancer research. Natural products and synthetic compounds have been searched extensively to cure different kinds of cancers and still search is on for finding novel compounds. Great effort has been done to find the target of anti-cancer drugs. Further target specific compound is being developed to cure cancer. Correlation between structure and function is one of the important aspects for success of anti-cancer compounds. In recent years strategic drug development program against the cancer has been initiated including high throughput screening of compound using bioinformatics, various cell lines, patient-derived tumor xenografts and drug delivery system. The purpose of this special thematic issue is to summarize the use of ongoing strategy for anti-cancer drug discovery and their valuable contribution for the expansion in the field of medicinal chemistry.

Microbial Bioinformatics is a rapidly evolving field of study that not only encompasses health and food science areas, but also presents new opportunities for advancement and innovation in engineering, manufacturing, and industrial process improvements [1]. As new sequencing methods become more cost effective and mobile, obtaining data for analysis is much less the obstacle than it once was [2-4]. The current resistance to widespread comprehensive data inclusion and diverse applied implementation of findings is the storage and computing power to analyze and organize raw data into usable and accessible formats. These hurdles will continue to be diminished with the improvement and application of new and more sophisticated algorithms as the artificial intelligence and cloud computing eases the current technological infrastructure burdens [5, 6]. The influx of omics data readily available for further analysis should be complemented by advancements in the structural modeling in order to ensure the structure-function relationships derived are sound. The complementary effect of greater sequence and structural refinement inputs serve to aid predictive elements as well as engineering of biomolecules, small molecule products, and in silico systems with medicinal or industrial purposes. Primary sequences dictate later modifications and structure [7]. To properly assess activity and function, the inclusive treatment of sequence, predicted modifications and corresponding structure, as well as the corresponding activities of such products in a systems perspective is imperative (Computational systems biology). Microbial systems have proven to be an invaluable simplistic model in systems biology, however when discussing medical microbiology in the context of antimicrobial design microbial system inputs are not easily directly transferable to human systems. This aspect may prove to be an advantage in development of antimicrobials that capitalize on these systematic differences in response to external perturbation (A network property necessary for concentration robustness.) Longevity, spectrum of coverage, and reduced toxicity of an antimicrobial treatment prove to be the difference between a theoretically good drug candidate, a later phase failure, and a true blockbuster global health improvement dictating medication. Precision medicine and pharmacogenomics is becoming more mainstream, as are more diverse and comprehensive microbial diagnostics becoming more affordable and accessible. The combination of systems analysis, structure-function relationships of small molecule drug candidates, and experimental findings from high-throughput screening and structural molecular dynamics validation methods provide improved stepping stones for drug discovery and development with expanded success limiting toxicity and maximizing the therapeutic effect [8, 9]. The complementation of experimental and computational sciences is ever apparent. As technological advancements in the areas of sequencing, data storage and acquisition, structural determinations, and systems biology arise, it is ever important that information is integrated and otherwise built upon for future studies to maximize available resources [10]. Funding, allocation of researchers’ time, and laboratory and computational resources need to be taken into account in order to maximize benefit while limiting redundancies that contribute to the lag between major findings in academia and their clinical implementation internationally. The academia to clinical availability factor of medicinally relevant small molecules will continue to improve, as will continually decreasing costs as more successful, promising leads are distinguished from less favorable leads earlier on and with greater ease in the drug discovery process [10, 11]. Distinguishing the winners from the losers earlier on in the drug discovery game will continue to contribute to less irrecoverable costs and less overall risk endured by drug manufactures in order to bring a new drug to market in an attempt to stay ahead of ever evolving microbial species presenting threats to human health globally, (Drug Delivery: Principles and Applications). 2. EXPLORING THE BIOLOGY AND STRUCTURAL ARCHITECTURE OF SORTASE ROLE ON BIOFILM FORMATION IN GRAM POSITIVE PATHOGENS Sortase enzymes are considered to be a powerful taught in all gram positive bacteria as it facilitates several functions including adhesions, internalins, blood clotting, immune evasion factors and transporters for nutrients across the microbial cell wall envelope. Due to its receptor availability, it is so called as universal drug target for gram positive pathogens. In present review Chandra Bose Selvaraj et al. they firmly explained a role of sortase in the virulence of pathogens and were focused on determining the role of Sortase enzymes' involvement in anti-infective studies and also, on the mechanisms of surface protein anchoring to the cell wall envelope by sortases, and highlight how it plays a strong role as drug target. Now it is considered as a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, evasion of host defenses, and biofilm formation. Many inhibitors of sortase have been identified using high-throughput or in silico screening of compound libraries, and also have proved useful tools for probing the action model of the enzyme, several are also promising postulant for the development into potent inhibitors [15, 16]. These research advances have greatly contributed to our knowledge of sortase cell wall anchoring, providing a platform for therapeutic targeting and further study in industrial applications. 3. ANTIFUNGAL ACTIVITY, MODE OF ACTION, DOCKING PREDICTION AND ANTI-BIOFILM EFFECTS OF (+)-β- PINENE ENANTIOMERS AGAINST CANDIDA SPP. Candidiasis is a most common fungal infection caused by yeasts that belong to the genus Candida. The antimicrobial activities of the isomers and enantiomers of pinene were evaluated against bacterial and fungal cells. In present study Ana Cláudia de Macêdo Andrade et al. exfoliated an example by using biochemistry and in silco approaches through molecular docking simulation and the effect on the biofilm reduction altogether to summarize, the mechanism of (+)-β-pinene most likely in interfering with the cell wall; maintain molecular interaction with Delta-14-sterol reductase and, to a lesser extent, with 1, 3-β-glucan synthase; is effective in the reduction of inhibition of the Candida biofilm [12-13]. (+)-β-pinene antifungal activity for effective to address candidiasis. Further, toxicological bioassays and phase I and II clinical trials are now needed to investigate the promising antifungal activity of the (+)-β- pinene as a potential candidate in the treatment of candidiasis which would be an innovative approach. 4. ANTIFUNGAL AND ANTIMICROBIAL PROPERTIES OF A PURIFIED PROTEASE INHIBITOR FROM MACROTYLOMA UNIFLORUM SEEDS Plant protease inhibitors (PPIs) are generally small proteins which play key roles in regulation of endogenous proteases and may exhibit antifeedant, antimicrobial, antifungal, antitumor and cytokine inducing activities. Macrotyloma uniflorum is an unexploited legume, which is rich in nutrients and promising therapeutic prospects. Manju Mohan et al. in the current study revealed the presence of a serine protease at active site. Future studies in this direction have to be performed to completely elucidate the characteristic features of Serine type protease inhibitor seed coat. The presence of protease inhibitor may be the cause for difficulty in human digestion and it’s role in processing antifungal and antimicrobial properties which can be used effectively for its application as a potential sea food preservative. An economical method to nullify the protease inhibitory activity which will increase the availability of a good protein source at a cheaper cost, thereby, making it a much needed protein source to meet the middle and lower class necessities [14]. 5. ANTI-HYERGLYCEMIC PROPERTIES OF A PURIFIED PROTEASE INHIBITOR FROM MACROTYLOMA UNIFLORUM SEEDS Hyperglycemia associated with diabetes mellitus is a major concern, which affects people with both type 1 and type 2 diabetes and be controlled by diet management, exercise, anti- hypoglycemic agents, and insulin therapy. Manju Mohan et al. in these current study evaluates anti-hyperglycemic activity of proteolytic enzymes purification which play central role in the biochemical mechanism of germination and is intricately involved in many aspects of plant physiology and development [17]. The inhibitory effect of purified protease on trypsin activity was characterized by enzyme kinetic study.To better understand the mechanism of protein mobilization, undertaken the task of purifying and characterizing proteases, which occur transiently. The overall study revealed that MUPI is an insulin sensitizer, and can be considered as a potent bioactive compound for diabetes. This innovative and challenging research will open up new avenues which constitute an effective anti-hyperglycemic protein which may find application in treatment of diabetes without evident toxic effects [18]. 6. STRUCTURE-BASED VIRTUAL SCREENING FOR THE IDENTIFICATION OF HIGH AFFINITY SMALL MOLECULE TOWARDS STAT3 FOR THE CLINICAL TREATMENT OF OSTEOSARCOMA Signal transducer and activator of transcription 3 [STAT 3] plays major role in cell signalling pathways, but over expression of this protein leads to osteosarcoma. STAT 3 is a latent cytoplasmic transcription factor which promote oncogenesis. STAT3 appears to be an important mediator of chemo resistance in osteosarcoma. Ravina et al. in the present study focus on decreasing the over expression of STAT3 protein by down regulating the pathway using chemical inhibitor to suppress STAT3 activity. Initial approach is made via in silico method based on docking studies and pharmacophore profiling to identify best pre-established compound [19-27]. Moreover a compound Sorafenib found to be best established drug with effective affinity towards the targeted protein. Interestingly, on further virtual screening investigation the total energy of virtual screened compound Pubchem CID-44815014 is better than the entire set of pre-established inhibitors with preferable affinity and inhibitory action. The study foresee Sorafenib and 44815014 are structurally cognate. Howbeit Sorafenib is efficient inhibitor, but novel compound 44815014 with great affinity towards STAT3 can be emerge as an important drug in treatment of disease the future ahead. Although, this research will open up new horizons to deliberate further utilization in in vivo and in vitro analysis. This research will contribute in determining the most effective chemical prospective to fight against osteosarcoma. 7. STRUCTURE-BASED VIRTUAL SCREENING APPROACH FOR THE IDENTIFICATION OF POTENTIAL ANTICANCER COMPOUNDS TARGETING CD20 FOR THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CD20 is a hydrophobic phosphoprotein commence on the surface of the human B lymphocyte cells, and play an essential role in the proliferation and differentiation of b-cells giving rise to humeral immune response, emerged as a tantalizing therapeutic option for the treatment of CLL. Kritika et al. in her study emphasis on determining drug which target chronic lymphocytic Leukemia (CLL) by constrain the activity of CD-20.Author rationalize the interaction of the CD20 with its pre-established inhibitors for CD-20 and to render the new compound having high binding consonance against the target protein. By virtue of Insilco approaches which includes depiction of targeted protein structure and validation by Ramachandran Plot [27-30]. Further docking studies carried out in addition with pharmacophore and ADMET analysis for toxicity [31-32]. Withal, conspicuous from the docking studies of pre-established and virtual screening [33-35] compound for CD-20 resulted in among all compounds top side with PubChem Id 36462 found to have good affinity among all pre-established compound for desired protein receptor CD-20, whereas on compelling this study virtual screened compound with PubChem CID-11753896 is inimitable for pharmacokinetics and it is preferable to pharmacological profile to prevent CLL cancer. This innovative and challenging research will open up new avenues which constitute an effective protein CD-20 which may find application in treatment of Chronic Lymphomatic Leukemia without evident toxic effects.

Epigenetics is the heritable change in gene function that does not involve changes in the DNA sequence. To date, several types of epigenetic changes have been characterized, including methylation, hydroxymethylation, acetylation, phosphorylation, ubiquitination, neddylation and so on. Most of these modifications can be read, written and erased on DNA, RNA and histone by specific modifiers. With the biological investigations of these modifiers, some of them are identified as promoters in the process of various diseases, such as cancer, cardiovascular disease and virus infection. Hence, targeting epigenetic modifiers has been considered as a promising strategy for disease treatment. To date, several epigenetic targeted drugs have entered clinic trials, or are currently being used in clinic, including a DNA methyltransferase inhibitor, bromo domain reader inhibitor, and histone acetylase or deacetylase inhibitor, histone methyltransferase or demethylase inhibitor, deubiquitinase inhibitor and neddylation inhibitor. Most of these drugs are applied in leukemia, lymphoma therapy, or are combined with other drugs for the treatment of solid tumor. This issue provides the up-to-date summary on some epigenetic targets and the development for related inhibitors for cancer therapy. The first review by Prof. Zigang Li and co-authors comprehensively summarized the biological roles of epigenetic targets and related inhibitors developed for cancer therapy. The second review by Prof. Weisheng Feng et al., comprehensively summarized the recent advances on the development of inhibitors targeting epigenetic targets, particularly those in clinical trials, and also gave their perspectives on the specificity, limitations and drug combination. The third review by Dr. Fanghui Lu et al., discussed HDAC inhibitors regarding their functional mechanism, the anti-tumor effects and potential clinical applications. The fourth review by Prof. Hao Fang et al., summarized recent advances on the structure and functions of HDAC6, and selective HDAC6 inhibitors. The last review by Prof. Feng Liu et al., summarized an array of nucleoside and non-nucleoside inhibitors of DNMTs, as well as their biological activities. I am grateful to all the researchers that contributed to this special issue and the referees for their insightful comments.

The important steps involved in the process of drug discovery are lead identification, lead optimizations, pre-clinical lead development, and clinical lead development. The contribution of computational design methods to lead identification and optimizations is no longer a matter of dispute. Exploitation of computational tools has not only reduced the cost but also the time in drug discovery. The last decade witnessed significant contributions of computational tools in many emerging areas of drug discovery viz. pharmacokinetics/pharmacodynamics, bioimaging, personalized medicines through system biology and drug repurposing. This special issue aims to cover the full spectrum of computational approaches relevant for drug discovery. Let us now discuss the content of this issue. The first review article is focused on the identification of drug binding sites and includes a comparison of three common approaches namely sequence-based methods, structure-based methods and probe-based Molecular Dynamics (MD) methods to identifying drug binding sites. Second review article is also related to hotspot/binding-site identification on protein surfaces, but this review article extensively talks about challenges and utilities of probe-based Molecular Dynamics (pMD) methods for the identification of small molecule binding sites. Third review article focus on current advances in the Fragment-based Drug Design (FBDD) approach. The subject of the following review article focusses on current status of application of ligand and structure-based approach targeting Anthrax virus. The last manuscript is a research article related to ligand and structure-based investigation of structural requirements for silent information regulator 1 [SIRT1] activation.

The important steps involved in the process of drug discovery are lead identification, lead optimization, pre-clinical lead development, and clinical lead development. The contribution of computational design methods to lead identification and optimization is no longer a matter of dispute. Exploitation of computational tools has not only reduced the cost but also the time in drug discovery. The last decade witnessed significant contributions of computational tools in many emerging areas of drug discovery viz. pharmacokinetics/pharmacodynamics, bioimaging, personalized medicines through system biology and drug repurposing. This special issue aims to cover the full spectrum of computational approaches relevant for drug discovery. Let us turn now to the content of this issue. The first review article talks about epidemics of viral diseases that adversely affects human population and the role of bioinformatic and immunoinformatic tools which can aid in vaccine design against these deadly diseases [1]. The second article is a review related to the recent advances and limitations of current pharmacokinetic modeling approaches and reveal some possible solutions to improve the applicability of in silico Caco-2 permeability models for absorption property profiling [2]. The subject of the following review article deals with the molecular modeling approaches for the prediction of pharmacokinetic properties [3]. Fourth review article offers us a vision on computational methods for binding mode and binding affinity prediction of peptide- MHC complexes [4]. The last manuscript is a research article related to lipid lowering, anti-oxidant and anti-hyperglycemic activity of oxopropanylindole hydrazone derivatives [5].

The interaction of with Medicinal Chemistry of new Enabling Technologies such as OMICS, Chem-Bioinformatics, etc., is expected to have a positive impact on the discovery of more effective and safe drugs. In this connection, Current Topics in Medicinal Chemistry journal is publishing a series of special issues entitled “New experimental and computational tools for drug discovery” to discuss all implications of this interaction in the broader sense. The series have published a total of four special issues up to date (1-4). The present issue is entitled: New Experimental and Computational Tools for Drug Discovery: Medicinal Chemistry, Personalized Medicine, Ethical, & Legal Issues. Part - V. In this sense, the issue presents a new collection of papers exploring the use of new methods of Medicinal Chemistry and Enabling Technologies in Drug Discovery. The issue also discusses the new aspects emerging from the interaction of Medicinal Chemistry with Personalized Medicine towards the development of safer personalized drugs in the future. In this connection, the issue also discusses not only chemical and technical methods but also ethical and legal concerns. The papers included in this part five can be summarized as follows: Clendenen & D’Alessandro pointed out that metabolomic analysis has made substantial contributions to the understanding of diverse pathological processes and has the potential to improve diagnosis and identify novel therapeutic targets. As early success in perinatal medicine, nutrition, chronic diseases, cancer and trauma demonstrates, metabolomics is approaching feasibility in terms of guiding improvement in population level diagnosis and treatment. This review covers key advancements in clinical metabolomics and applies a high throughput metabolomics method as a proof of principle to identify novel metabolites associated with remote ischemic preconditioning [1]. Malik et al. focused on the development of xanthine oxidase and monoamine oxidase inhibitors leading to important breakthroughs in the therapy of oxidative damage, hyperuricemia, gout, neurological, neuropsychiatric disorders and management of reperfusion injury. Drugs obtained from natural sources play an important role in treatment of various pathological disorders and act as lead compound for the discovery of new synthetic drug substances. In this review various pharmacological effects produced by inhibition of xanthine oxidase and monoamine oxidase through natural and synthetic flavanoids as well as anthraquinones are discussed in detail. In this review, all the in-vitro and other computational approaches are critically discussed which provided the clue about structure activity requirements for further precise modifications on the basic scaffold [2]. Duardo-Sánchez & De Miguel Beriain highlighted that Medicinal Chemistry and Personalized Medicine related to it, has received a great attention in recent years. Significant investment and remarkable researches surround the matter; however, not all those promising advances are reaching patients as quickly as they should. The absence of an adequate regulatory framework could be not helping. The complete and/or massive sequencing of individual genomes faces many ethical-legal challenges. Some of them are the access to Personalized Medicine; the treatment of a large volume of sensitive information and the use of tools produced by "big data" systems in clinical care or in predictive models. In addition, the legal protection of personal data related to health, the exercise of autonomy by patients, closely related to the regulation regarding clinical trials, are seriously involved. The purpose of this work is to review the regulations of the European Union, in this regard [3]. Sharma et al. pointed out that Renal Cell Carcinoma is a common type of renal cancer-causing deaths worldwide is characterized by sustained angiogenesis. Induction of VEGF genes occur due to hypoxic condition induced by tumour growth after a critical size in cancerous cell. Signal transduction networks originated by VEGFA/VEGFR2, (a notable ligand-receptor complex in the VEGF system) leads to major angiogenesis events ranging from endothelial cell proliferation, to new vessel formation. Furthermore, differential expression of VEGFVEGFR mRNA also found in different types of RCC. The aim of present study is to inhibit the VEGFR2 protein by the action of certain inhibitors and find the best one. A total of 23 potential inhibitors were searched and used to target the protein using the concept of molecular docking. The compound SCHEMBL469307 predicted have a high potential to inhibit the VGFR2 protein and can be backed for future studies in Renal Cell Carcinoma [4]. Ferreira et al. discussed that the increase in the prevalence of drug-resistant pathogens occurs at a time when the discovery and development of new antimicrobial agents occur slowly. In this context, the objective of this study was to investigate the antifungal activity of isoeugenol, a phenylpropanoid, by in vitro and in silico assays against Penicillium citrinum strains. For in silico analysis, the software PASS online, Molinspiration and Osíris were used. For the determination of Minimum Inhibitory Concentration (MIC) and Minimal Fungicide Concentration (MFC) of isoeugenol and voriconazole were carried out using the broth microdilution technique. PASS online has shown that isoeugenol has the opportunity to present antiseptic, antifungal, antibacterial, antimycobacterial activities. Molinspiration showed that the phytoconstituent has good potential for oral bioavailability. The MIC of isoeugenol varied between 256 and 32 μg/mL, MIC50 of 64 μg/mL and MIC90 was 128 μg/mL. After analysis, it was verified that the isoeugenol have bactericidal effect against the strains of P. citrinum [5].

Infectious diseases, such as endocarditis, chronic skin infections, middle ear infections and sinusitis are responsible for over 15 million deaths a year [1]. The high mortality rate is due to the widespread use of antibiotics in humans which cause increased resistance by bacterial strains. Microorganisms can induce antibiotic resistance by several mechanisms: hydrolysis or chemical modification of the antibiotic through the production of enzymes, alteration of the antibiotic target site, decrease in membrane permeability and/or increase active efflux of the antibiotic, and modification of the metabolic pathways to circumvent the antibiotic effect [2]. Moreover, bacteria in biofilms communicate by means of molecules, which activate genes responsible for the production of virulence factors (quorum sensing mechanisms). Current antibiotic therapy is generally effective against free-floating bacteria while it is often unproductive against pathogens forming biofilms because biofilm colonies can be up to 1000 times more resistant to conventional therapies [3]. Increasing resistance to antibacterial agents has augmented the need for the development of new drugs and drug delivery approaches to treat infections [4, 5]. Investigations concerning the development of novel strategies to overcome antibiotic resistance represent a great challenge for both the academic world and industry since bacterial infections represent a significant issue that includes several areas such as public health or food contamination [6, 7]. This issue highlights the chemical and pharmacological features of novel compounds to treat antibacterial infections and recent therapeutic approaches to overcome antibiotic resistance. The papers included in this special issue confirmed the importance of both well-known natural products with low molecular weight and antimicrobial peptides in the management of chronic and nosocomial infections. However, natural antimicrobial peptides and polyphenolics derivatives could suffer from chemical instability, photosensibility, and enzymatic degradation, which hamper their clinical use. Here, to overcome these limitations, medicinal chemistry approaches, such as chemical modifications, replacement of hydrolysis sensible groups or introduction of mimetics of natural amino acids, were analyzed and reported. Thus, this special issue collects latest advances in the field of antibacterial drug discovery and delivery such as the use of natural-based antibiofilm and antimicrobial peptides, naturally occurring prenyloxyphenylpropanoids, and polyphenolics as suitable clinical tools for the treatment of infections. The guest editor wishes to thank all the researchers that contributed to this special issue and the anonymous reviewers that, with their helpful and constructive suggestions and comments, improved the quality of the final version of the papers.

Infectious diseases cause remarkable human suffering, particularly in lowincome and middle-income countries. Infectious diseases are responsible for the vast economic burden globally. Efforts are going on to develop effective and safe therapeutics, however the rapid appearance of drug resistance in human pathogens, weaken the clinical worth of several current drugs. Therefore, the discovery of new anti-infectious molecules is highly demanded. This special issue comprises the up-to-date information on drug development for infectious diseases. The first contribution presents a review article focused on small molecules effective against liver and blood stage malarial infection was contributed by Dr. Singh and her co-workers from Miranda House, University of Delhi, India. This mini-review article covers library of chemical compounds effective against blood stage and liver stage malarial infections (i.e. dual stage activity). The second contribution was received from Prof. Samuel K. Kwofie and colleagues. This review focuses on the malarial aspartic proteases known as Plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins. The group led, Prof. Alo Nag and co-workers from University of Delhi South Campus, India contributed the next review article about ionophores as potent anti-malarials. This review presents an overview on the state-of-the-art of the relevant literature on ionophores, and provides insight into the mechanism and prospects of different classes of ionophores as promising antimalarial. Next, two articles were contributed by Prof. Ramesh Chandra and his team members from University of Delhi North Campus, India. The biological aspects of heme and its drug interactions with CYP450 have been reviewed. The last contribution is an research article that presents the designing of a novel indoline scaffold based antibacterial compound and pharmacological evaluation using chemoinformatics approaches. We are grateful to all the authors and referees for their valuable support to this special issue.

Research to discover new treatments for infectious disease has developed as a specialty during the past century. At global level, the burden of the infectious diseases is growing, particularly in low-income and middle-income countries, and susceptible populations. Infectious diseases trigger millions of deaths yearly. Widespread resistance of anti-infectious drugs remains a big threat, particularly when effective vaccines are not available for most of the infectious diseases. Subsequently, inventions of new therapeutics effective against infectious diseases are highly required. This special issue of Current Topics in Medicinal Chemistry contains the latest updates on molecular mechanisms, drug targets, drug development for infectious diseases in the form of high-quality articles from the various parts of the world. The first contribution presents a review article focused on antibiotics-peptide conjugates from the research group led by Dr. Rakesh K Tiwari, Chapman University, USA. This article deals with the advanced information on antibioticspeptide conjugates (APCs) extensively, as an approach to battle the threat of multi-drug resistance of bacterial pathogens. The adopted APC strategies and physicochemical properties that show how they can be used to increase the antibacterial efficacy are also discussed in detail. Next contribution deals with chemistry and biology of farnesol and its derivatives was prepared by Dr. Krishna Mohan Poluri from Indian Institute of Technology Roorkee, India. This interesting review discusses the biological roles, chemical-biochemical synthesis, metabolic engineering, and crucial biotechnological uses of farnesol based compounds. The third contribution entitled internet resources for drug discovery and design was received from Prof. Maria Grishina, South Ural State University, Russia. This comprehensive review highlights the possibilities of the internet resources for a study of a drug action at the most important stages. Also, a detailed assessment of advantages of the reviewed internet resources is presented. The fourth article entitled chemotherapeutic potential of monensin as an anti-microbial agent, presented by Dr. Vinoth Rajendran and co-workers deals with the therapeutic potential of monensin as a new broad spectrum anti-microbial agent that permits further investigations for clinical use. The last review article on apicoplast metabolism: parasite’s Achilles’ heel was contributed by Dr. Manmeet Rawat and co-workers from University of New Mexico, USA. This article describes the cardinal features of the methylerythritol phosphate (MEP) pathway enzymes and progress made towards the characterization of new inhibitors. MEP pathway is described as a repertoire of novel anti-malarials and antibacterial drug targets. The Guest editors are highly thankful to all the authors and referees for their valuable support to this special issue. Science and Engineering Research Board (SERB), Govt. of India is acknowledged for financial support (ECR/2015/000448). YK is grateful to the Department of Science and Technology (DST-SERB), Ministry of Science and Technology, India for financial support (YSS/2015/001966).

As it has already been stated [1, 2], basic neuroscience research is prevented from instrumentation into direct clinical application due to several methodological limitations, concerning extrapolation, penetrability and objectivity of the methods. In other terms a large part of neurobiological inquiry, including studies of neurochemical pathways, drug targets and mechanisms remain relatively discrepant from clinical utility. In this special issue there has been delivered strong evidence on the potential use of tetramethoxyluteholine and umbelliferone as treatment agents for neurodegenerative and neuropsychiatric disorders. However rather fundamental pharmaceutical perspective (drug synthesis) have been employed by Dhiman et al. [3] whilst Theoharides and Tsilioni [4] embrace more medical stance, with an emphasis on the drug target mechanisms in the cytokine-neuropeptide interactions. Further there has been achieved remarkable advance into in-vivo imaging of the underlying neurochemical processes in mental disorders which essentially provide insights beyond the aforementioned limitations of the traditionally adopted neuroscientific methods [2]. Those are in particular the methods of functional neuroimaging. Most promising progress in the application of magnetic resonance spectroscopy in the study of the metabolites involved in the pathogenesis of schizophrenia has been summarized by Dwyer et al. and for functional magnetic resonance imaging results with memory evaluation paradigms in bipolar disorders by Beshkov et al. [5]. This field of research is linked directly to the studies of novel molecular pathways implicated in various mental disorders [6, 7]. The bottom line message from our Special Issue is that the advances in applied neuroscience research bring together large scale experimental data sets spanning from neurochemical to neurophysiological and behavioral levels of explanation which should gradually aspire towards in vivo real time investigations of the biological substrate behind neurological and psychiatric disorders.

Design and development of new drugs is extremely expensive and resource-intensive process. During the past few decades, computer-aided drug designing/ discovery has played a major role in designing of new drugs in a cost-effective manner. Computer-aided drug designing utilizes concepts of structural/ chemical biology to efficiently identify and optimize lead compounds using computational tools and methods. Structure-based and ligand-based drug designing approaches are commonly employed for virtual screening/ identification of lead compounds or to improve the therapeutic potential of an existing lead compound. Homology modelling, virtual screening, quantitative structure-activity relationships (QSAR), density functional theory (DFT), molecular docking, molecular dynamics (MD) simulation and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions as well as systems biology approach aids in the drug development process. This thematic issue is aimed to illustrate the pivotal role of computational techniques in unravelling the structure-function relationship to understand the molecular recognition events of target macromolecule with ligand leading to the design of improved lead candidate for the target receptor.

Applied neuroscience includes contributions and insights from neuro-biochemistry, molecular neurobiology, neuroimmunology, neuropharmacology and among others. The present topic embraces a complex multi-dimensional interface between basic neuroscience innovative study designs, novel molecular and bio-chemical markers and drug targets; advanced computational technologies and their implementation in clinical neuropsychiatry. It will address as well the interplay of complex neurobiological factors and psychosomatic disorders

Neglected Diseases are those that affect almost exclusively poor and powerless people living in rural parts of low-income countries [1]. They sometimes attract other labels, such as tropical diseases or poverty-related diseases. Neglected diseases include leishmaniasis (kalazar), onchocerciasis, Chagas disease, leprosy, tuberculosis, schistosomiasis, lymphatic filariasis, African trypanosomiasis (sleeping sickness), malaria and dengue [2]. Some are lifethreatening, while others result in high morbidity and severe disabilities [1, 3]. Currently some of these tropical infections have become a major global concern, due to serious sequelae; as Zika Virus and Ebola. Also, geographical distances between continents do not represent a barrier to infectious agents due to rapid transport. Infected human hosts can travel facilitating epidemics. The objective for this thematic issue was to report recent studies about different approaches in drug discovery, which comprises synthesis, semi-synthesis, the search for new targets, natural products, evaluation of biological activities, and/or theoretical approaches as structure-based approaches, SAR, QSAR, docking and several cheminformatics methods [2], for investigation and selection of new lead molecules. These efforts involve several studies to aid the drug discovery of new options for the treatment of neglected diseases. Dengue like any neglected tropical disease affects a large part of the world population. In this disease, the infection is caused by arboviruses transmitted by A. aegypti and A. albopictus mosquito, in which the most severe manifestation is known as dengue hemorrhagic fever. The infected person presents symptoms characteristic of fever and rash. Among the ways of fighting dengue by bioactives is the inhibition of NS2B-NS3 protease, inhibition of protein E, and inhibition of sclerotization of the vector cuticle. The cuticle is indispensable for the survival of the mosquito that can be compromised through the inhibition of arylalkylamine N-acetyltransferase (aaNAT). In our manuscript entitled Dengue Virus Inhibition Targets: A Review and Docking Study, in silico tests were performed as molecular docking, functional density analysis, molecular orbitals energies and of the interactions between the bioactive and the targets studied were analyzed. However, in addition to discussing the fight against dengue virus infection through different routes, some in silico results of 27 analogs of myricetin have been presented, which showed action on the cuticle sclerotization mechanism. Dengue Fever: A Worldwide Threat: An Overview of the Infection Process, Environmental Factors for Global Outbreak, Diagnostic Platforms, and Vaccine Developments by Hosseini et al, is a review article also focused on Dengue. The paper covers essential topics including an overview on neglected tropical diseases with specific emphasis on Dengue fever, mosquito's cycle of life and mechanism of infection, adaptive response, and different stages in Dengue immunopathogenesis. The current work is also dedicated to the thorough study of Dengue outbreak across the globe with a brief study of tropical and subtropical regions. Moreover, this review article demonstrates the correlation between the climatic factors and Dengue incidence. In the manuscript entitled, Discovery of Potent Inhibitors for the Inhibition of Dengue Envelope Protein: An In Silico Approach, Aarthy & Singh showed a study with the crystal structure of Dengue Envelope protein from the protein data bank optimized through Schrodinger. The structure based virtual screening based on the co-crystallised ligand has been carried out with the small molecule libraries and based on the docking score, interaction and energy values, best complexes were selected. The selected complexes were further taken forward for the conformational stability analysis through Molecular dynamics simulation. From the results it is evident that the compounds DB00179, Quercetin, Silymarin, Dapagliflozlin and Fisetin could be novel and potent candidates to inhibit the DENV envelope protein. Many of the tropical diseases are neglected by the researchers and medicinal companies due to lack of profit and other interests. The Drugs for Neglected Diseases Initiative (DNDi) was established to overcome the problems associated with these neglected diseases. According to a report published by the WHO, leprosy (Hansen's disease) is also a neglected infectious disease. The treatment used until now for leprosy is multi-drug treatment. The complete genome identification of Mycobacterium leprae makes the research easy to develop target specified drugs for leprosy. Rifampicin, identified as a potent drug, along with other drugs in uniform multi-drug treatment, has a significant effect when given to leprosy patients at initial stages. These are effective treatments but a specific drug for leprosy is still needed to be identified. The review of Aamir et al., Recent Advancement in the Diagnosis and Treatment of Leprosy, highlights the use of modern methods for the identification of leprosy at its earlier stages and the effective use of drugs alone as well as in combination. The manuscript of Hazra & Patra entitled Alleviating the Neglected Tropical Diseases: Recent Developments in Diagnostics and Detection discussed various novel research progresses/advancements made for qualitative and quantitative measurement of infectious load in some diseases like dengue, Chagas disease and leishmaniasis; though further improvements in the specificity and sensitivity front are still awaited. Strategies to combat the problem of antimicrobial drug resistance in the diagnosis of NTDs have also been put forward by various research groups and organizations. Moreover, the state-of-the-art “omics” approaches like metabolomics and metagenomics have also started to contribute constructively towards diagnosis and prevention of the NTDs. The aim of the study by Khan and co-workers, Formulation and Characterization of a Self-Emulsifying Drug Delivery system (SEDDS) of Curcumin for the Topical Application in Cutaneous and Mucocutaneous Leishmaniasis, was to develop a Self-Emulsifying Drug Delivery System (SEDDS) for the hydrophobic polyphenol pigment curcumin to enable it for its potential use in cutaneous and mucocutaneous leishmaniasis. The results demonstrated that the SEDDS formulations of curcumin have the potential to provide a promising tool for curcumin for its use through topical routes in the treatment of these diseases. Through virtual screening of a chemical library of 15,123 small molecules, analyzed by two programs, four potential inhibitors of phosphoglycerate mutase 1 from P. falciparum were found by Rios-Soto et al. The study was reported in the manuscript entitled Virtual Screening, Molecular Dynamics and ADME-Tox Tools for Finding Potential Inhibitors of Phosphoglycerate Mutase 1 from Plasmodium falciparum. Molecular dynamic analysis revealed that these molecules interact with residues important for enzyme catalysis and molecule ZINC04343691 provoked the highest structural changes. Physiochemical and toxicological profiles evaluation of these inhibitors with ADME-Tox method suggested that they can be considered as potential drugs. Furthermore, analysis of human PGAM-B suggested that these molecules could be selective for parasitic enzymes. In the manuscript of Thomas & Timson, entitled The Mechanism of Action of Praziquantel: Some Hypotheses; the authors discussed that there is a critical need to understand the biochemical pharmacology of the praziquantel in order to inform the discovery of the next generation of anthelmintic drugs. We, the Guest-Editors, would like to express our gratitude to the many authors who contributed to this special issue, reporting investigations of various aspects of Recent Advancement against Neglected Diseases.

Heterocyclic rings are considered the pillars of medicinal chemistry because they are merged into the molecular structure of most of the available therapeutic drugs in the market. Since the early days of medicinal chemistry, these rings were known to be important as structural feature responsible for the relationship between structure and biological activities. Taylor et al. [1] estimated that approximately six new ring systems are created per year and that some of these are incorporated into new drugs. According to the authors, 1,2,4 and 1,2,3-triazoles are among the top 100 most frequently used ring systems from small molecule drugs listed in the FDA orange book sorted by descending frequency. The sub-class of five-membered heterocycle [2-4] is widespread in nature [5] as well as in the therapeutic arsenal available to treat various diseases [6]. In addition, they have several representative drugs in the market for the treatment of disease as antifungal, anticancer, antiviral, β-lactamase inhibitor, anticonvulsant and antibiotic agents [7-11]. This special issue is based on seven manuscripts dealing with recent advances in the application of triazoles derivatives for treatment against infectious disease. Forezi et al. [12] reported a review covering synthetic methods that give access to other variations around the 1,2,3-triazole core. The systematic arrangement in this review explores the possibility of providing practical guidance to alternatives of this heterocycle. It has been divided into sections according to the types of starting materials and reactions. Heterocyclic rings having nitrogen atoms are the molecular fragments mostly used in drug design by using the tools of medicinal chemistry. Souza and colleagues [13] synthesized a series of naphthotriazolyl-4-oxoquinolines that exhibited potent in vitro antileishmanial activity involving at least two different mechanisms of action, making them promising lead compounds for the development of new therapeutic alternatives for leishmaniasis. Branco and coworkers [14] synthesized a series of naphthotriazolyl-4-oxoquinoline derivatives and tested their activity against a human breast cancer cell line. Among the compounds tested, a molecule was identified that killed the human breast cancer cell line MCF-7 with minimal effects on its healthy cell MCF10A. The selectivity observed against breast cancer cells make the molecule 12c a potential candidate as a novel anticancer drug. The antitumor mechanism involves the inhibition of glycolysis, diminished intracellular ATP levels, induction of ROS production and triggering of apoptosis. These effects are all selective for cancer cells, since the healthy cells are unaffected, and these effects can only be attributed to the whole molecule since different groups do not reproduce the effects. Reis and coworkers [15] prepared a series of symmetrical 1,4-disubstituted bis-1,2,3-triazoles by double Copper Catalyzed Azide-Alkyne Cycloaddition (CuAAC) from aliphatic bis-azides and a tetraethylene glycol bis-azide derivative. The novel compounds were evaluated in vitro for their cytotoxic activity against two human tumor cell lines: human breast adenocarcinoma (MDA-MB 231) and ovarian adenocarcinoma (TOV-21G). The results showed that some compounds exhibited a better selectivity index and cell viability comparable with the standard drug doxorubicin. These compounds induced apoptosis in both tested cell lines. The results suggest that these compounds may be promising prototypes for antitumor agents. Imbroisi-Filho and coworkers [16] tested several novel triazoles compounds for their putative anticancer activity and one molecule (DAN94) presented selective effects on cancer cells with minimal effects on non-cancer cells. The anticancer effect occurs through the disruption of mitochondrial potential which induced the production of ROS, triggering cell apoptosis. In parallel, cells are arrested on G1/G0 phase of the cell cycle, decreasing the ability of these cells to proliferate. On top of that, when administered to mice with xenograft tumors, DAN94 strongly reduced tumor growth with no toxic effect. These results suggested that DAN94 is a good candidate for anticancer drug due to its selective effects on cancer cells and should be tested in a pre-clinical trial. Costa et. al. [17] synthesized two series of the compounds containing 1,2,3-triazoles ring in their structures and biologically evaluated novel inhibitors of HIV Reverse Transcriptase (RT). The results of the biological evaluation showed that all compounds presented high RT inhibition values and lower or comparable inhibitory concentrations. Thus, new compounds could be considered lead compounds for the development of new antiretroviral compounds. Lal and coworkers [18] synthetized sixteen new hybrids and were tested in vitro for their antimicrobial activity. Some of the tested compounds exhibited promising antimicrobial activity and could be utilized for the development of the new and more potent antimicrobial drugs. All these publications confirm the importance of triazoles scaffold in the search for new biologically active compounds.

The classical methods of diagnosis in both parasitology and mycology require microscopic visualization as well as the identification of the microorganisms using their morphological characteristics. In addition in the case of fungi, it is necessary to use culture-based methods. However, these methods are tedious and usually not very sensitive and require trained personnel to perform them. Tools for the diagnosis and monitoring of the disease remains a challenge, since a diagnosis is misleading, erroneous or too slow, hinder effective treatments. As a result, new and low-cost assays are required to help physicians to establish an accurate and definitive diagnosis and to modify the strategies to control these infectious diseases. Alternatively, indirect methods have been developed, such as serology-based assays and more recently molecular- based assays. In this respect, this CTMC thematic issue includes extensive reviews of updated diagnostic methods. Recently, molecular techniques based on the amplification of nucleic acids have allowed the development of sensitive, specific and rapid diagnostic methods, however their high price and the requirement of infrastructures make difficult to apply them in low-resource countries. Dea-Ayuela et al. have analysed the main advances in the development of a molecular technique called Loop-Mediated Isothermal Amplification (LAMP) assay for the diagnosis of malaria, leishmaniasis and Chagas' disease as well as the feasibility of their implementation in developing countries and its use as point-of-care diagnostic tests [1]. Candida is a fungus that is present in the skin, mouth or intestine of healthy individuals whose growth is controlled primarily by the immune system. However, in certain circumstances, such as immunosuppression, the infection spreads to different organs causing an invasive candidiasis. Pitarch et al. compiles an extensive review of the diagnostic methods applied in the most serious forms of candidiasis, the invasive one, since the rapidity in making the correct diagnosis is fundamental in the control of the infection and the prognosis of the disease [2].

Infectious diseases are caused by bacteria, viruses, fungi and parasites and are one of the leading causes of human morbidity and mortality, being also responsible for huge economic losses in the livestock industry. Among the control measurements of infectious diseases are the correct diagnosis and the adequate treatment of patients or/and asymptomatic carrier. Unlike other pathogenic microorganisms, parasites and fungi are eukaryotic organisms, so their cells are very similar to human/animals cells, making necesary to search and develop drugs without side effect or toxicity to the hosts cells. The fungal and parasitic infections have a wide global distribution, however the therapeutic arsenal available in the XXI century remains extremely reduced, this problem is aggravated by the appearance of resistance to conventional treatments. Due to the indifference of pharmaceutical industry, non-profit organizations, such as universities or research centers, are doing an exhaustive effort in the identification of compounds with antiparasitic and antifungal activity. There are different approaches in the search for new drugs, such as High-Throughput Screening Tests (HTS), which allow for the evaluation of thousands of different biological compounds through robotic systems, the identification of the mechanism of action and subsequent development of compounds with the same mechanism, or computer-aided design that includes structure-activity studies or virtual screening, among others. On the one hand, the complexity of the host-parasite system makes that compounds with good activity in in silico and in vitro models do not correlate with good efficacy in vivo, either because they do not reach the parasite per se (many parasites are intracellular or are anatomically isolated) or because the parasite has different forms with different responses to the compound. Since these pathogens have accompanied mankind since many years and hence, there are numerous ethno-pharmacological and ethno-botanical data that support the use of different plants in the treatment of the infections produce by parasites and fungi. Some of them are collected in traditional Chinese medicine, Ayurvedic or in the traditions of various indigenous groups from different parts of the world. Due to the difficulty of accessing conventional drugs in many developing countries, WHO has included among health strategies the incorporation of traditional medicine (complementary and alternative) to health systems, as long as there are clinical investigations that guarantee its safety and efficacy. This CTMC thematic issue includes extensive reviews related to the natural, conventional and advanced pharmacological treatments of various fungal and parasitic infections. Passero et al., reviewed several studies to understand how active products obtained from plants can be used in the treatment of leishmaniosis, with special emphasis on those from Brazil. Vivancos et al., make an extensive review about the treatment of Giardia intestinalis, from conventional pharmacological treatments to the use of medicinal plants, probiotics and new formulations with the aim to reduce the appearance of resistance and toxicity. Several parasites are responsible for diseases in livestock and involve large economic losses. Sanchez-Sanchez et al., examine the different measures applied in the control of Toxoplasma and Neospora, responsible for abortions in livestock with special emphasis on chemotherapeutical guidelines taking into account the different stages of the parasite and the safety for the final consumer. Candida is a part of our habitual microbiota, however in certain circumstances it can behave like an opportunistic pathogen, generating from skin and mucous infections to serious invasive forms. González-Burgos & Gómez-Serranillos analyze clinical evidence on the effectiveness of natural products in the vulvovaginal candidiasis, including essential oils, honey and yogurt or plant extracts. Finally, Taborda et al., focuses on two of the most important systemic mycoses, paracoccidioidomycosis and histoplasmosis, and their major characteristics in epidemiology, clinical aspects, treatment and laboratory diagnosis.

To rush to edit a special issue requires a lot of energy, motivation and constancy. When we started to consider the idea, it seemed a quite complicated challenge because our day to day struggle, as well as the authors and collaborators, were already strenuous. However, after many talks and discussions we decided to start this project. Various factors acted as detonators of our determination. We believe that the modern University cannot be just a factory of employees, but of people committed to the community and to the culture. In this particular case, we speak of the scientific culture but with the widest possible sense, making it a support of our humanity itself. The implementation of these foundations configures the hegemony of certain relational and understanding principles, of a vision of science, the life and the world. Beyond the particular positions and the over-meant local conditions that envelop all that remains within their reach, the moment we currently live allows us to identify the planetary expansion of scientific thoughts, risky theoretical and practical approaches. They all acquire countless forms allowing the apparent difference to be valued and signified. Unraveling this avalanche of progress and events is not only a necessity for knowledge, but a social urgency in the face of global conditions. As new generations are integrated into science, it is imperative to convey knowledge to them. This gives a community wherein the other is heard, developing strong links between the old and young generations. It is now time to analyze the two points of maximum relevance in these special numbers: the focus of the publication and the target audience. With regard to the first, we have focused on works that sketch modern settings and particular allusions to topics that under our point of view we consider the most relevant. At this time, we can guarantee that the chosen works include some of the most avant-garde proposals and initiatives, in tune and synchrony with the spirit of the publication. These articles are contemporary reflections that reread the present and open horizons beyond rigid and inflexible schemes. But not without giving up scientific rigor and, above all, the interconnection between different branches of knowledge. The second point to take into account focuses on the potential audience. When a publication with several authors and points of view assumes an expositive function it is difficult to specify the limits of that audience without having the idea of each one of the contributors. Such standpoint offers different approaches, which do not stop evolving, just like the audience itself. As an example, communication channels, audience profile and continuos increase of the multidisciplinarity make it difficult to homogenize the perspective. That is why we have tried to guarantee a wide outlook of the subject, seeking to ensure the authors to introduce their subjects with a general and accessible style and increasing the complexity and depth of the study progressively. We thus guarantee the possibility that each reader will extract the appropriate information and adjusted to their specific needs. Let us turn now to the content of this issue. The first manuscript has been reserved for both of us, as editors. Our goal was to introduce the general subject and make a critical view of the state of the art. We know that the biopolymers are the fundamental basis of chemical medicine and try to encompass everything is impossible. Therefore, we decided to organize the work focusing on their interactions with different types of materials (organic and inorganic) and the most technologies used: bulk and microfluidics. The next article is a review related to the development of new classes of antibacterial drugs. This review is focused on the worldwide problem provenient from bacterial resistance that will generate 10 millions deaths per year in 2050. The authors present different topics the reason for the decreased development of antibacterial agents, current strategies in antibacterial drug development, new mechanisms of action, and clinical development. The third article focuses on a computational vision on physicochemcial properties of biopolymer-material complexes. It offers a wide and contemporary vision of computational techniques with the most impact on biomedicine, more specifically: a combination of machine learning techniques and perturbation theories. The subject of the following article deals with the mechanical properties of biomaterials. Areas focused on tissue engineering or bone regeneration are not understood without the knowledge of the mechanical properties of the constituents. In this study the authors introduce us in the field of rheology by studying and analyzing some of the most important bioceramics in medicine. We shall turn to the next manuscript, a review that is focused on the most relevant colloidal drug delivery systems describing the effects of surface charge, hydrophobicity on bilogical response and the different strategies to modify the surface of organic, inorganic and biological materials. The sixth chapter offers us a vision on the structure and hierarchy of collagen not only from a biological perspective but also explains its potential applications in medicine. The seventh article is focused on the function of allyl isocyanate (AITC)-loaded Polylactic-co-Glycolic Acid (PLGA) as anticancer. The targeting ability was tested in HeLa cells demonstrating more effective anticancer properties compared with free AITC and their citoxicity was even more pronounced when a anti-EGFR antibody was covalently attached to the NPs surface. Additinally, the importance of this manuscript is that the proposed system (antibody-functinalized AITC-loaded PLGA NPs) was especifically located in squamous carcinoma A431 cells in comparison with non-functionalized NPs that were distributed randomly. The last manuscript is a research article related to two new materials for the encapsulation of bioactive compounds as carvacol: Pectin (PEC) and Aloe-gel (AG). The authors characterize this PEC/AG film for different techniques demonstrating the optimal concentration to microencapsulate carvacol.

Aims & Scope: Burgeoning rise in different disease cases such as cancer, viral diseases including Dengue, Chikungunya, Zika, Ebola, Japanese encephalitis, etc., other tropical and neglected diseases, metabolic conditions such as diabetes and many other health conditions warrants the need of immediate investigations and end the human plight for ensuring a better tomorrow. Advances in scientific research have shown the impact in eradication and prevention of many diseases conditions such as polio. Interplay of experimental and theoretical approaches have come a long way in proving their effectiveness and worth in this regard. Earlier computational approaches were almost ignored by a large section of the scientific community. Last few decades have witnessed a drastic change in the existing beliefs and today theoretical techniques are not only supporting and supplementing experimental results but also guiding studies by providing valuable cues. Computational approaches pertaining to understanding complex biological system have come a long way during past few years rising from its infancy to blooming into a full-fledged science. Simple bioinformatics and chemo-informatics approaches are being frequently applied in the arena of system biology and are providing remarkable insights on unsolved and unanswered scientific questions so far

At present, with the continuous development of bioinformatics, computing technology has been successfully applied in all aspects of pharmacy and medicine. Among them, the identification of drug-target interactions, synergistic drug combinations and drug repositioning based on heterogeneous biological data and powerful computational models are important topics in computational biology. Research on these important issues is not only for a better understanding of the various interactions and biological processes, but also for the development of new drugs and the improvement of human drugs. Previously, drug research faced an important problem that was difficult to solve. Since multiple targets usually involve the same disease, following a single disease, a single target, a single drug paradigm does not have the desired effect on accelerating drug discovery. Recently, in order to improve drug efficacy and overcome problems before drug resistance, the development of multi-target drugs has received much attention. It is well known that despite drug-target interactions, experimental assays for synergistic drug combinations and drug repositioning are very valuable and have made significant contributions to drug research, but the technical challenges make these experiments time consuming, expensive and limited to small scale studies. Surprisingly, computational methods can provide new predictions for experimental scientists and narrow the scope of candidates to accelerate drug discovery. Therefore, the development of a powerful method for the effective detection of potential drug-target interactions in a genome-wide manner, synergistic drug combinations and drug-disease associations is urgent. Using these computational models to obtain potential predictions with higher scores, and implementing biological experiments to verify, will greatly reduce human and material resources. The following pages of this issue are seven papers presenting current application of computational techniques in pharmacy and medicine, representing only a small portion of current research. The following is a brief description of these papers. In the opening paper of this issue, Muhammad et al. comprehensively presented the latest advances in drug target interaction identification methods and their use in drug multi-pharmacology [1]. In the second review, Ding et al. summarized the latest advances in computational methods for predicting effective drug combinations in a number of ways, including various datasets for discovering synergistic drug combinations, feature-based similarity measures and machine learning methods, as well as web-based methods that reveal synergistic drug combinations. In addition, the calculation method for predicting effective drug combinations was analyzed and predicted in this article [2]. Zhang et al. discussed current knowledge about ncRNA and network pharmacology-regulated genes involved in pulmonary arterial hypertension, as well as potential drug targets for pulmonary arterial hypertension [3]. Zhang et al. comprehensively reviewed the drug toxicity prediction studies based on machine learning in recent years, and compared the performance of the models proposed in these studies in terms of accuracy, sensitivity and specificity, providing the current state-of-the-art in this field and highlighting the issues in the current studies [4]. Wang et al. outlined the structure-based drug design used in drug discovery and highlighted its recent successes and major challenges of the current structure-based drug design approach [5]. Hao et al. summarized common methods for using protein-protein interaction networks to aid disease research and drug discovery, including network topology analysis, identification of new pathways, drug targets, and subnetwork biomarkers for disease [6]. Dong et al. discussed in detail the progress of parallel acceleration molecular docking software based on different common high performance computing platforms. Not only is the existing suitable program optimized and ported to the high performance computing platform, but many novel parallel algorithms are also designed and implemented. In addition, this article focuses on the techniques and methods used to parallelize docking software and recommended exemplar case studies [7]. We would like to express our sincere gratitude to all authors and reviewers for their contribution to this issue. We would also like to extend our appreciation to the Editor-in-Chief, Dr. Allen B. Reitz and the editorial staff of Current Topics in Medicinal Chemistry for their excellent support and providing us with the opportunity to pursue this hot topic issue.

Enabling technologies like Computational Chemistry, Bioinformatics, Combinatorial Chemistry, Metabolomics, Proteomics (OMICS in general), etc., are expected to speed up the discovery of more efficient and safer drugs in Medicinal Chemistry. Recently, this journal has launched a series of special issues focused on this topic. The title of this series of special issues is: New experimental and computational tools for drug discovery: From chemistry to biology. Four (1-4) special issues are currently available. In these issues, experts from around the world discuss the state-of-art and/or report new methodologies. The methodologies focus on organic synthesis of new lead compounds, the in silico screening of new lead compounds, computational discovery of drugs from natural compounds isolated from plants, the repurposing of known drugs, re-engineering of cost-effective medicines, nano-systems for drug release, etc. The present issue is entitled: New experimental and computational tools for drug discovery: From chemistry to biology. Part 4. Metabolomics, Pharmacokinetics, and Medicinal Chemistry. Part 4 is the continuation of the series and provides six papers focused on new technologies used in drug discovery, but this time with emphasis on Metabolomics, Pharmacokinetics, and Medicinal Chemistry. The papers included in Part 4 can be summarized as follows: Gross et al., [1] point out that metabolomics experiments generate a rich array of complex high-dimensional data. They suggest that this may, in part, account for past and more recent incomplete replications of previously specified biomarker panels, especially if not adequately considered. Herein, they identify common impediments challenging the analysis of raw, targeted Metabolomic abundance data and review methods that may remedy these issues, based on personal experiences and those of others. In doing so, they propose an analytical pipeline suitable for the pre-processing of data prior to downstream biomarker discovery. González-Domínguez et al., [2] present work focused on intervention and observational trials as complementary tools in Metabolomics. The authors provide a review of the literature regarding the application of metabolomics in assessing metabolic alterations with diabetes, diabetic insulin resistance, and provide an oral glucose tolerance test case study to demonstrate the complementarity of observational and interventional study designs. Kataria et al., [3] presented a work on the role of morin in Neurodegenerative Diseases (NDDs). NDDs are known to cause profound effects on families and patients, and a tremendous financial burden on the healthcare system of most populations worldwide. Morin, being a super antioxidant compound, may help prevent and mitigate such disorders by suppression of Reactive Oxygen Species (ROS) and through the inhibition of multiple additional targets. In this review, the authors discuss various neuropathological conditions and their specific target sites that may be relevant to morin’s neurobiological mechanisms. Bueso-Bordils et al., [4] focused on obtaining microbiological and pharmacokinetic predictive equations. They reviewed the state-of-art in the area and also reported a new study. Multi-Linear Regression (MLR) analysis was carried out in order to accurately predict physicochemical properties and biological activities on a group of antibacterial quinolones by means of a set of structural descriptors called topological indices. The aim of this work included developing prediction equations for such properties, after reviewing the relevant literature on antibacterial quinolones. De Sousa Eduardo et al., [5] focus on the requirement of research related to new antimicrobial agents, as increasing numbers of microorganisms expressing antibiotic-resistance are emerging. In this paper, the authors review the topic and also pro- De Sousa Eduardo et al., [5] focus on the requirement of research related to new antimicrobial agents, as increasing numbers of microorganisms expressing antibiotic-resistance are emerging. In this paper, the authors review the topic and also provide verification for the activity of a phytoconstituent against Escherichia coli strains ATCC 25922 and Staphylococcus aureus ATCC 25923. The authors recommend further investigations, utilizing different methodologies assessing whether (+) - α- pinene may provide an effective compound in future antimicrobial therapy. Srivastava et al., [6] focused on the inhibition of biofilm and virulence factors associated with Candida albicans by the partially purified secondary metabolites of Streptomyces chrestomyceticus strain ADP4. Despite several advancements in antifungal drug discovery, fungal diseases, such as Invasive Candidiasis (IC), remain associated with inordinately high rates of morbidity and mortality worldwide. In this paper, chemical profiling indicates that ADP4 secondary metabolites contained potentially beneficial alkaloids, flavonoids, polyphenols, terpenoids and triterpenes. The authors also report other experimental and computational findings.

Infectious diseases are still one of the main cause of mortality and morbidity worldwide. In addition, antimicrobial resistance is a well-recognized global threat; hence, necessitates the development of tough policies to control the spread of disease-causing microorganisms coupled with antimicrobial stewardship strategies and new therapies to reverse this process. In order to fight against microbial infections, we need new antimicrobials. Much effort has been infused by the scientific community in the past to the search of new and potential antimicrobials. Researchers have explored antimicrobials based on plants, microorganisms, and even synthesized new compounds. This issue deals with the important developments related to the topic of antimicrobials, especially, plant-based antimicrobials, β-lactamase inhibitors, new synthetic drugs, and also about the target based drug delivery system in case of chemotherapeutic agents. Singh et al. have discussed the importance of plant antimicrobials of the past decade (2007-2017). As plants are the major contributors of vast number of compounds, the plants have remained the indispensable source of medicine, and thus plant based antimicrobials are important to be considered. Most of these compounds are produced as secondary metabolites and their medicinal properties may be beneficial for the human being also. The synthetic chemistry has offered various molecules but most of these are directly or indirectly related to some plant source. In the current review, they have presented the plant-based antimicrobials reported between 2007 to 2017. Genera where most of the researchers have concentrated during this period includes, Thymus, Helichrysum, Quercus, Jatropha, Gnaphalium, Acalypha, and Lippia. Some other miscellaneous gene on which one or two reports are available include, Conocarpus, Chamaesyce, Bucida, Boehmesia, Pancratium, Artemisia, and Cinnamosma [1]. Wang et al. emphasized the development of β-lactamase inhibitors as potential antimicrobial agents. Horizontal transfer of the genes encoding metallo-β-lactamases (MBLs) among Gram-negative bacteria pathogens has led to the emergence of drugresistant pathogens, which now represent a major threat to the human health. It is urgent to develop new antibiotic agents to fight against antibiotic resistance. Metallo-β-lactamases (MBLs) are an important class of Zn(II)-dependent enzymes that can hydrolyze almost all β-lactams and render bacteria resistant to antibiotics in the clinic. To date, there are no clinically available MBL inhibitors although a large number of MBL inhibitors have been identified. In this review, they have highlighted the recent developments in small-molecule MBL inhibitors in the past decade [2]. Kaur et al. synthesized and characterized a new series of diazenyl chalcones by combining the azo and chalcone moiety together and evaluated them for antimicrobial and antioxidant potential. Some of the derivatives had shown high antimicrobial and antioxidant activity as compared to the standard drugs and hence presented new lead compounds for the development of novel antimicrobial agents [3]. Conventional chemotherapeutics lack the specificity and controllability, thus may annihilate healthy cells while attempting to annihilate cancerous ones. Newly developed nano-drug delivery systems have shown promise in delivering anti-tumor agents with enhanced stability, durability, and overall performance; especially when used along with targeting and triggering techniques. Ahmed et al. traced back the history of chemotherapy, addressing the main challenges that have encouraged medical researchers to seek a sanctuary in nanotechnological-based drug delivery systems that are grafted with appropriate targeting techniques and drug release mechanisms. A special focus will be paid towards acoustically triggered liposomes encapsulating doxorubicin [4]. As a whole, all these papers illustrate the versatility of this topic and highlight the importance of developing new prospection tools to advance the discovery of new compounds. I want to thank Bentham Science Publishers especially, the Editor in Chief Dr. Allen B. Reitz, who provided me the opportunity to contribute this thematic issue on such a topic and also all the editorial members for their continued support and cohesive interactions. I express my highest gratitude to all the contributing authors for their commitment, subject expertise, dedicated work, healthy coordination and support to me throughout the issue. I would also like to pay special thanks to all the reviewers for spending their valuable time on critical analysis of the manuscripts and providing valuable suggestions for further refining the manuscripts. At last, I am also thankful to all our readers.

Infection or colonization, contrary to what many people think, does not necessarily imply immediate damage to the host. From birth, beneficial microorganisms coexist and develop within us for a long time. However, when such organisms cause damage to the host body, an infectious disease with the associated symptoms and pathology is contracted. From a clinical point of view, a pathogen is any microorganism capable of developing as an infectious disease; where differences in pathogenicity depend on virulence. Infectious diseases caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi can spread, from person to person, directly or indirectly and throughout a community. The studies united in this issue demonstrate the efforts of research to combat such infections and reduce the social cost of these diseases. Antimicrobial resistance is a major global concern. Strains of Tuberculosis (TB) resistant to rifampicin and other drugs challenge patient survival and public health. The World Health Organization (WHO) [1] has issued treatment guidelines for drug-resistant tuberculosis since 1997, and last updated these guidelines in 2016 based on the assessments of patient data in both published and unpublished studies. As the first choice for patients assailed by Multiple Drug Resistant Or Rifampicin Resistant (MDR/RR) strains, WHO recommends a standardized treatment regimen of from 9 to 12 months. Mycobacteria are characterized as slow-growing bacillus having a cell wall composed of highly lipophilic mycolic acids. The nature of this cell wall is of most importance to the development of new candidates for anti-tuberculosis (anti-TB) drugs. Mycobacterium tuberculosis is an intracellular pathogen highly adapted to its natural host: the human. Its cell wall, consisting mainly of mycolic acids, forms a hydrophobic barrier that confers resistance to both desiccation and discoloration by alcohol or acid. In our review, entitled Multi-Target Antitubercular Drugs, we reported the discovery of 3 classes of compounds that can simultaneously interact with more than one target of Mycobacterium tuberculosis. Increased incidences of Candida infection have augmented morbidity and mortality in the human population, particularly among severely immunocompromised patients and those having a long stay in hospitals (nosocomial infections). Many virulence factors and fitness attributes are reported to be associated with the pathogenicity of Candida sp [2]. It can cause infections ranging from easily treatable superficial type to life-threatening invasive infections. Additionally, it has the capability to infect humans of all age groups. Indeed, overutilization of broad-spectrum antibiotics has further complicated the scenario by leading to the emergence of less sensitive Candida strains, especially non-albicans. Despite our developed armamentarium, the diagnosis and treatment of human fungal infections remain a challenge. The review of Dr. Srivastava and co-workers entitled Emerging virulence, drug resistance and future anti-fungal drugs for Candida pathogens, focused on the prevalence of Candida spp. as human pathogens with emerging resistance to existing anti-fungal drugs. Furthermore, factors and mechanisms contributing to the pathogenicity of Candida spp. and the challenges being faced in combating the devastating infections associated with these pathogens have been discussed. Also, pros and cons of the current and future anti-mycotic drugs have been analyzed. Current study assesses the in-vitro antimicrobial activity of the crude extract of D. retusa (whole plant) and its derived fractions against clinically isolated human pathogenic bacteria and fungi [3]. In the manuscript Evaluation of In-Vitro Antimicrobial Potential of Daphne retusa Hemsl. against Human Pathogenic Bacteria and Fungi, Dr. Nawab et al. studied D. retusa as powder dried Extracted with methanol (E1). The study showed that D. retusa had a very good inhibitory action against different bacterial and fungal strains. All of the extracts were active almost against every microorganism used in the study. E2 has maximum percent inhibition against bacterial growth while E1 has maximum percent inhibition against fungal growth. Streptococcus pneumonia was the most susceptible bacteria while among fungi, Gongronella butleri showed the highest susceptibility. Onion (Allium cepa L.) and garlic (Allium sativum L.) extracts are traditionally used in many cultures as antimicrobial agents. Nonetheless, there is still a dearth of scientific validation pertaining to the antibacterial and possible antibiotic potentiating activity of these plants [4]. In the work Onion and garlic extracts potentiates the efficacy of conventional antibiotics against standard and clinical bacterial isolates of Dr. Mahomoodally and co-workers, decoction as traditionally used and methanol, ethanol, ethyl acetate, and acetone extracts of onion and garlic were evaluated for their antibacterial activity against 15 bacterial strains (6 ATCC strains and 9 clinical isolates) using the broth microdilution method to establish the minimum inhibitory concentration. The bacteriostatic and bactericidal actions were determined as compared to conventional antibiotics (streptomycin and chloramphenicol). Fractional Inhibitory Concentration (FIC) was determined to establish any synergistic interaction between the extracts and antibiotics using a modified checkerboard assay. The observed antibacterial activity might be justified due to the presence of high concentration of phenolic compounds in the extracts. This study has provided an opportunity to establish valuable baseline information on the antibiotic potentiating activity of onion and garlic, which can be further exploited for the treatment and/or management of infectious diseases. Some research has shown that Lippia pedunculosa Essential Oil (EOLP) has interesting biological activities. However, its low water solubility is the main challenge in achieving its therapeutic potential [5]. In this context, Cyclodextrins (CDs) have been widely used in order to overcome this problem due to their capability to improve the physicochemical properties of drugs. In this perspective, the main goal of the study of Dr. Menezes et al. entitled Physicochemical characterization and antinociceptive effect of β -cyclodextrin/Lippia pedunculosa essential oil in mice was to investigate how the improvement in the physicochemical properties of inclusion complexes (EOLP and β-CD) enhances the antinociceptive effect in mice. We, the Guest-Editors, would like to express our gratitude to the authors who contributed to this special issue, reporting investigations in various aspects of Perspectives on Infectious Diseases: Progress and Therapeutics.

The discovery that the members within a protein complex are not only found in close proximity but also talking to each other has expedited development of both experimental and computational techniques, which are used for studying protein-protein interactions (PPIs). The former provides information regarding the existence of the interaction and it also helps on the identification of the interaction interface. In spite of emerging roles of PPIs as novel drug targets for treatment of various crucial diseases over the past decade the field is still far from having a holistic understanding of the mechanism of interaction. Therefore, experimental techniques should guide and/or complement computational studies in order to develop efficient therapeutic molecules having higher affinity and lower side effects. In this special issue, we aim to summarize recent experimental and computational techniques used for studying PPIs as well as their possible application on selected biological problems of great significance in an effort to development of novel drugs that target PPIs. Among many others NF-kB, NSP1, MDXM, GPCRS, CD-40, BAFF-BAFF-L are some of the systems that have been revised.

Cyclic peptides and peptidomimetic molecules (modified peptides) play critical roles in natural processes, and can also be synthesized for use as research tools and therapeutics. Protein-Protein Interactions (PPIs) play central roles in regulating almost all biological processes across organisms and the central dogma of biology. Compared to small molecules and antibodies, peptides are advantageous for targeting PPIs because they maintain conformational flexibility, can be synthesized using relatively straightforward techniques and are generally less expensive. However, linear peptides are limited by poor stability and inefficient cell membrane permeability. On the other hand, cyclic peptides offer improved metabolic stability, bioavailability and selectivity compared to their linear counterparts; moreover, cyclic peptides are particularly useful for targeting PPIs because they maintain these enhanced drug-like properties without compromising bioavailability, as often occurs with linear peptides. Thus, the development of cyclic peptides and peptidomimetics is of great interest in medicinal chemistry, as evidenced by numerous investigational and approved cyclic peptide pharmaceutical compounds. This thematic issue is comprised of six strong papers authored by esteemed colleagues renowned for their work in the field of medicinal chemistry. The overarching topics covered include cyclic peptides in natural and therapeutic settings, the design of cyclic peptides, several approaches to synthesize cyclic peptides, and examples of cyclic peptides in biological systems. First, Rubin and Qvit present the first comprehensive review, analysis and critique of backbone-cyclized peptides, discussing their design, construction, development, and application. To address the construction of backbone-cyclized peptides, Rubin, Tal- Gan, Gilon, and Qvit subsequently provide a detailed guide for the conversion of protein active regions into peptidomimetic therapeutic leads – delineating the identification of PPI sites, the definition of bioactive pharmacophores and the use of backbone cyclization and cycloscan techniques to develop lead compounds. Next, Perez reviews additional approaches for design of peptidomimetics and discusses their core properties, while comparing and contrasting the medicinal chemistry and biophysical approaches for discovery and development. Testa, Papini, Chorev and Rovero extensively discuss approaches to synthesize cyclic peptides and peptidomimetics, including in depth analysis of the chemistries required to perform ring closing metathesis, lactamization, copper-catalyzed azide alkyne cycloaddition, and other cyclization reactions. Following this, Hillman, Nadraws and Bertucci delve into stapled peptides and focus on recent advances in their use for targeting PPIs therapeutically. Lastly, Mull, Harrington, Sanchez, and Tal-Gan present examples of cyclic peptides in biological systems through an analysis of cyclic peptide scaffolds in signal transduction pathways across a spectrum of prokaryotic and eukaryotic organisms as models for the discovery of novel and broadly applicable therapeutic lead compounds. It was an honor to compile this timely issue. Thanks to the journal for providing the opportunity for our colleagues and us to share our perspectives. We hope the readers find this material engaging and useful, and that it will inspire further inquiry and applied works.

Cancer metabolism is an emerging area of research that offers an opportunity to target specific metabolic vulnerabilities of cancer cells. Cancer cells undergo oncogene-mediated metabolic reprogramming in order to meet their energy demands. Cancer cells adapt to their microenvironment and rewire their metabolism to rely heavily on anaerobic glycolysis, a phenomenon known as the ’Warburg effect’. In addition, cancer cells get addicted to glutamine and also up regulate fatty acid synthesis to support their survival and rapid proliferation. Recently, there has been a resurgence of interest in targeting carbohydrate, amino acid, and fatty acid metabolic pathways for treatment of cancer and overcoming drug resistance in chemotherapy. Other emerging concepts include targeting mitochondrial metabolism for the treatment of cancer. The overarching theme of this issue is to highlight the current application, advances, and emerging concepts in the field of cancer metabolism and discuss the prospects of metabolic inhibitors as next generation cancer therapeutics. The issue will also emphasize medicinal chemistry efforts aimed at developing small molecule inhibitors targeting aberrant cancer metabolism.

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The term "alternative" is employed to describe the test method in association with the principles of the 3Rs - Replacement, Reduction and Refinement. In accordance with this principle, an alternative method can be used to replace animal testing, reduce the quantity of animals required for each assay, or refine an animal testing method to minimize pain and suffering. There are different platforms available to create alternative methods including in vitro models and computer-based systems. A few elements may be considered in terms of safety when it comes to the development of a new drug or biomaterial. First it is important to identify the chemical identity and the composition, as well as chemical structure, impurities and functional groups, followed by the determination of the physical chemical properties. As a next step, the kinetics aspects, e.g. absorption, distribution, metabolism and excretion should be evaluated. The mode and /or mechanism of action or adverse outcome pathways as well as the chemical and biological interaction must be determined. Finally, the responses found in alternative assays can lead to a proper safety assessment for drugs and biomaterials without the need for animal experimentation. Within this context, this thematic issue focused on alternative assays applied to replace animal testing in order to assess the safety and biological activity of currently available and novel drugs and biomedical devices. The manuscript entitled "Epithelial organotypic cultures: a viable method to address the mechanisms of carcinogenesis by epitheliotropic viruses" describes the mechanism of carcinogenesis, a topic that was initially researched mainly in animal models. In another context, some alternative methods have also been employed in biomaterials, as the authors of “Current Methods Applied to Biomaterials – Characterization Approaches, Safety Assessment and Biological International Standards” extensively described. This review shows that using alternative tests for biomaterials has almost replaced animal tests, following an actual tendency. Finally, the last two manuscripts, “Validation cytotoxicity assay for lipophilic substances” and “Alternative methods to animal studies for the evaluation of topical/transdermal drug delivery systems” are important both for medicine and cosmetics formulation, as the authors showed the importance to characterize the lipophilic substances, even a difficult issue in cytotoxicity assays, and the importance of permeation in cosmetics and medical products. Overall this special issue has addressed aspects concerning alternative assays applied to replace animal testing in order to assess the safety and biological activity of currently available and novel drugs and biomedical devices and contain materials that follow the topics in trends and published worldwide. This issue shows balanced viewpoints of experts contributing to minimize the use of animal tests, in an attempt to act as a primary reference for industrial, commercial and research perspective in an extensive field of science.

Head and neck squamous carcinoma (HNSCC) is the sixth most common malignant cancer in the world and it is characterized by a poor prognosis. In fact, the estimated survival rate is 5 years from diagnosis. The prognosis of the disease is significantly related to the stage in which the disease is diagnosed. Moreover, the therapies are too invasive and not very efficient, disfiguring and debilitating the survivor’s quality of life which is much compromised. Nowadays, there is not a reliable and non-invasive method for early diagnosis of oral squamous cell carcinoma and the simple visual examination of the oral cavity is characterized by low sensitivity and specificity, also because the early stages of oral carcinogenesis are not associated with clear clinical abnormalities in a significant number of patients. The current issue of “Current Topics in Medicinal Chemistry (CTMC)” is aimed at reviewing the actual knowledge regarding the HNSCC in order to cover this field with a broad series of papers. The first review was prepared by an Italian team led by Fatima Ardito, Giovanni Di Gioia, Mario Roberto Pellegrino and Lorenzo Lo Muzio. The authors describe the role of genistein as a potential anticancer agent against HNSCC. The second contribution is from Linda L. Eastham, Candace M. Howard, Premalatha Balachandran, David S. Pasco, and Pier Paolo Claudio. In this case, the authors review the role of dietary phytochemicals as an alternative approach to prevent HNSCC. The third review, led by Riccardo Concu and Maria Natalia Dias- Soeiro Cordeiro, deals with the role of the Cetuximab in the treatment of HNSCC. The fourth contribution concerns the Aurora kinase inhibitors in head and neck cancer; this work was prepared by a Chinese-Japanese team led by Guangying Qi, Jing Liu, Sisi Mi, Takaaki Tsunematsu, Shengjian Jin, Wenhua Shao, Tian Liu, Naozumi Ishimaru, Bo Tang and Yasusei Kudo. Moving on, Nicola Sgaramella and Karin Nylander review covers the topic of searching for new targets and treatments in the battle against squamous cell carcinoma of the head and neck. Concu and Cordeiro present an innovative paper dealing with the development of a new QSAR model aimed at the identification of new inhibitors for the epidermal growth factor receptor. Finally, Ardito et al. present a new in vitro study of the inhibition activity of the curcumin against squamous cell carcinoma of tongue.

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