New Avenues in Drug Discovery and Bioactive Natural Products

Nature contains a huge array of unique phytomolecules, many of which have previously evolved into lead compounds and have been transformed into herbal formulations or are currently undergoing clinical studies. Plant-based pharmaceuticals account for 25% of all drugs on the market, either directly or indirectly. The herbal drug sector has gotten a lot of attention in recent years, which has resulted in its exponential rise. People increasingly prefer herbal treatments to synthetic drugs, highlighting their safety and efficacy. Standardization of these herbal medications has become a significant component of the process involved in herbal drug development, not just for Asians but also for westerners, due to increased interest. The role of various analytical methods, such as chromatographic methods, spectroscopic methods, metabolomics, DNA barcoding, and so on, has been explored in this chapter. These methods aid in not only authentication but also quality assurance during the herbal medicine research process.

Drug discovery relies on screening for bioactive components in natural sources, such as bacteria, fungi, and plants. Bioactive natural products and secondary metabolites provide the main source for developing new therapeutics, serving as new antibiotics and anticancer agents. With identifying the first biosynthetic genes over the last few decades, scientists now have the tool at their disposal to better understand the genetics and logic behind these biosyntheses. In addition, in this genomic age, one can have access to an increasing number of genomes for reproducible research outcomes. Genome mining, in conjunction with synthetic biology, has become significantly more relevant to drug discovery. In the current chapter, the main aim is to explore how the recent trends of genome mining and synthetic biology approaches can be used to discover novel natural products while highlighting both the benefits and drawbacks of these techniques. We also consider the adjacent methods for the validation of data after genome mining. By reviewing the literature, an attempt was made to finally summarize all-natural drugs obtained by genome-mining from fungi, bacteria, and other microorganisms. 

Herbs have been used as medicines from ancient times in the world. In the present scenario, awareness and acceptability towards herbal medicines have been raised tremendously due to their easy availability and few or no side effects. Unfortunately, due to the lack of stringent regulatory guidelines for herbal drugs, standard quality degradation may be associated with these herbal medicines through either intentional or unintentional adulterations, spurious drugs, the substitution of drugs with other drugs, etc. Hence, it becomes mandatory to control the quality standards of herbal medicines as they are being used for the betterment of human health. Improvements in various domains of herbal medicine have helped developed countries, such as USA, UK, Australia and European countries, adopt this ancient and enriched medicinal system leading to the “Herbal Renaissance”. Herbal medicines, however, are associated with a number of shortcomings such as quality assurance, safety, efficacy, purity, lack of appropriate standardization parameters, lack of accepted research methodology and toxicity studies. Despite the availability of numerous traditional quality control methods (e.g., thermal methods, HPTLC, HPLC, SFC) for herbal medicines, owing to the lacunae, there is a prerequisite for newer approaches in fostering quality parameters of herbal drugs. Chromatographic and spectral fingerprinting, DNA fingerprinting and metabolomics can be used as newer approaches to the authentication and standardisation of medicinal botanicals. Currently, the computational In-Silico technique for standardization of phytochemicals is in trend because of the number of pros like less time consumption, fast, and improved efficiency of the entire process with excellent reproducibility.

Herbal medicines are emerging as the bliss of the modern era for the treatment and welfare of the population owing to their safety, and minimum or lack of side effects. Keeping this perspective in mind, the quality of herbal medicines is equally important as allopathic medicines. To thwart the adulteration of herbal medicines with substandard or similar low-grade herbs is the prime objective of standardization for the maintenance of the quality of herbal medicines. Assessment of quality and purity of crude drugs using several parameters such as morphological, microscopical, physical, chemical & biological evaluation can be performed through standardization technique. A number of conventional standardization methods are available, but owing to their lackings in one or more aspects, modern standardization techniques are being opted for by many researchers nowadays. Amid all the novel standardization techniques, DNA fingerprinting method is the most important in the quality control of herbal medicines on account of its accuracy and consistency. DNA fingerprinting defines barcode-like DNA fragment patterns generated by multilocus probes after the electrophoretic parting of genomic DNA fragments. Hence, this chapter primarily emphasizes on DNA fingerprinting method as a tool for the standardization of herbal medicines.

Emerging disease threat and the mortality rate associated with it has triggered the need for the identification of treatment and prevention of such diseases. Natural products are known for here therapeutic value and can act as a prominent source for the identification of new drugs for these diseases. Many different strategies have been developed to identify and obtain newer drugs from natural resources. Natural products are a potential source of drugs for many diseases due to their structural diversity and already reported biological activity. Lead compounds for many lethal diseases, such as the recently emerged infectious disease COVID-19 have been identified using computational techniques which may help to curb the COVID-19 outbreak. Omics-based techniques such as proteomics, genomics, metabolomics, transcriptomics, etc, have become one of the most helpful techniques for discovering drug products from natural resources. CRISPR is another such technique that combines bioinformatics, genomics and synthetic biology. It is a DNA-targeting genome editing tool that has aided medical research. Other than these, many more drug discovery tools such as multi-omics, combinatorial biosynthesis, artificial intelligence and 3D printing have been a boon for identifying natural products with diverse chemical structures and therapeutic indexes. Advanced computational techniques have helped develop potential drug candidates with desired therapeutic activity. This chapter focuses on recent computational techniques employed to discover drugs from natural resources. 

Nature has bestowed our universe with a vast wealth of restorative and curative plants. In the 21st century, medicinal plants' therapeutic effects have been considered a promising future drug/medicine for managing health care. The phytochemicals in herbs are the active ingredients that possess therapeutic activity and are considered medicine or drug. The ever increasing demand for phytochemicals from plant origin, either as pure compounds or as standardized extracts, provided unlimited opportunities for new drug leads. Seeking therapeutic drugs from natural products is of particular interest throughout the world. Plants synthesize secondary metabolites, which include alkaloids, flavonoids, saponins, terpenoids, glycosides, tannins and volatile oils. One of the important phytochemicals to be discussed in this chapter is glycosides. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzymatic or acid hydrolysis leading to one or more sugar moieties along with non-sugar moieties. The former is called glycone, and the latter is aglycone or genin. Based on sugar moiety linkage, they are classified as C-glycosides, O-glycosides, S-glycosides and N-glycosides. Due to the complexity of plant chemical constituents, pure phytochemicals must be obtained using proper extraction and isolation techniques. This chapter focuses on the analytical methodologies, which include the extraction, isolation, identification and characterization of glycosides from medicinal plants.

Natural medicines and traditional remedies are pretty valuable. Ayurveda, Traditional Chinese medicine, and Unani have all been practised in various parts of the world and have grown into well-organized medical systems. Secondary metabolites such as alkaloids, flavonoids, and tannins have already established their anti-microbial, anti-diabetic, and anti-cancer attributes. Mikania is one such plant genus used in folk medicine, which belongs to the Asteraceae family and is native to Central and South America. Still, it is extensively dispersed in Southeast Asia and Pacific Islands. Phytometabolites, viz., mikanolides and achalensolide, have emerged as potent antineoplastic agents. Sesquiterpene lactones such as deoxymikanolide and mikanolide possess anti-microbial activities. Apart from sesquiterpenes, several phenolic compounds comprising (+)-isolariciresinol and protocatechuic aldehyde were found in the aerial parts of Mikania micrantha. Antifungal activity of essential oil containing βcaryophyllene, δ-cadinene, and α-cubebene was characterized by GC/MS and isolated from Mikania scandens. Various steroids and diterpenoids obtained from Mikania cordata exhibited potent analgesic activity. This plant also contains germacrene D, βpinene, and α-thujene, characterized by GC/MS. Many phenylpropanoids, sesquiterpenes, and diterpenes obtained from Mikania laevigata were characterized using NMR and mass spectrometry. Lupeol, lupeol acetate, and kaurene diterpenes were derived from Mikania glomerata and validated using RP-HPLC methods.

COVID-19 has been a threat to the whole world due to its massive amount of infectivity. The causative SARS- CoV virus has an extremely small biological footprint. However, it has the ability to bind with the host cell, which, in this case, the human upper respiratory tract, with the intervention of a minimal amount of enzymes and energy. For this anchoring, this virus uses a specially designed protein known as the spike protein or S-protein which also gives the virus its unique shape. Unfortunately, even after the discovery of the vaccine, the number of people getting it is still significant. This is due to the ability of the virus to prevaricate immunity through constant mutation. Therefore, the search for an antiviral drug is still necessary. While there are only a few identified targets of anti-SARS-CoV drug designing, the S-protein can be unique for two reasons; first, it can be both virostatic and can be used as a postexposure prophylaxis measure. Here, in this book chapter, we look into several drugdesigning techniques that can be utilized for designing a molecule that can prevent the first stage of infection, and that is to attach with the ACE receptor of the host cell using the S-protein. Both ligand-based and structure-based designs have been taken into consideration, with a special focus on lead molecules obtained from natural products.

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. Type 2 diabetes mellitus (T2DM) is typically characterized by insulin resistance, wherein there is a cross-talk involving obesity and inflammation. Symptoms of T2DM include polyuria, polydipsia, and weight loss, often accompanied by polyphagia, blurred vision, growth impairment, etc. The disease burden is often complicated by secondary complications like retinopathy, nephropathy, peripheral and autonomic neuropathy, increased incidence of atherosclerosis, peripheral and cerebrovascular diseases. Advances in understanding the pathophysiology involved in disease progression have led to the exploration of novel targets like glucose transporters, incretin-based therapies, SGLT-1/SGLT-2 modulation, AR/PTP1B dual inhibitors, PPAR-based therapies, NFκB and modulation of IRS for the management of T2DM. Various in vitro and in vivo studies have strongly suggested the potential of phytochemicals for the treatment of different pathological conditions associated with hyperglycemia and its complications. Different secondary metabolites have shown promising results in the treatment of different metabolic disorders, including T2DM, by different mechanisms of action. This chapter aims to provide an overview of some of the major phytochemicals, currently investigated for their potential activity against T2DM along with the mechanisms contributing to glycemic control. 

Natural products have historically made a significant contribution to traditional and modern medicine and are considered one of the most successful new structural leads and effective drug development sources. Secondary metabolites and their structural analogues produced by suitable chemical or biological modifications have helped significantly to discover new lead molecules from herbal medicines. Moreover, 34% of prescription drugs are from plant-based or semi-synthetic derivatives, which include anti-cancer, anti-Alzheimer's, anti-hypertensive, anti-psychotic, infectious diseases and immunosuppressive molecules. More than 80% of people worldwide rely on herbal medicinal products and approximately 60% of clinical medicines are prepared from natural resources. This book chapter deals with the introduction to the phytochemical investigation, the significance and systematic steps involved in the phytochemical investigation, characteristics of phytoconstituents, selection of solvents, solvents influence and extraction procedure of natural products and treatment of plant residue after extraction. Further, the application of in silico molecular docking studies for the phytoconstituents detected from medicinal plant extracts to identify novel possible lead compounds against disease therapeutic targets. The key steps that enable natural product-based drug development and discovery with recent technological advancements are summarized.

 Colon cancer is the third most frequently occurring and second most deathcausing disease in the entire world. Even though there is rapid development in the treatment, there is a high increase in the death rate of colon cancer. The current treatments available for colon cancer are not specific and are mainly associated with numerous toxic effects. Hence, developing novel drug treatments with desired characteristics to treat colon cancer patients is in huge demand. In case of novel drug discovery for various kinds of dreadful diseases like cancer and neurodegenerative diseases, medicinal and plant-derived components also play a significant role. Here, in this review, we have chosen andrographolide, a potent bioactive compound that shows multiple pharmacological actions such as anti-inflammatory, antiviral, antioxidant, hepatoprotective and neuroprotective effects. In addition, it also shows anticancer effects against various types of tumours along with colon cancer. In this review, we aimed to describe in detail the effect of AG and its analogues in colon cancer by identifying its possible drug targets. Thereby, it develops a chance to qualify AG as a novel drug candidate for colon cancer in the near future.

Currently, analytical techniques play a crucial role in drug discoveries and isolation processes. Different advanced methods are available for screening natural resources into desirable forms. Among them, chromatographic techniques are the most reliable and applicable for small quantities of samples. Chromatography is a technique for separating mixtures that depend upon differential affinities of solutes between two immiscible phases. One of the phases is a fixed bed of a large surface area while other fluid flows through or over a fixed phase. The greatest utility of chromatography lies in its ability to separate mixtures of solutes so that several individual substances may be quantities isolated in a pure state. Separation and identification of a natural substance can be challenging. Natural substances are a mixture of different components with different physiochemical properties. They are available as natural sources in large to small quantities in the form of a mixture. Herein, we are trying to explain different types of chromatographic techniques and types of strategies adopted to identify and isolate natural substances.

Mother nature has provided us with a vast array of plants to be utilized as medical remedies. Since ancient times, natural products have been and continue to be a fertile source for the development of novel medicines and therapeutic leads, and various research data conclude that more than 50% of the drugs in the market are derived from natural resources, highlighting the importance of herbal medicine in today's era. Recent research on medicinal plants has led to the rediscovery of longknown effects at the cellular and molecular levels. The absence of standardized procedures in older investigations shows up in situations of biological activity. Furthermore, traditional medicines with plant origins may be used as additional treatment alternatives to treat various illnesses. More research is needed for a solid knowledge of the herbal medicine system combined with current science that may enlist functional leads foundation for deadly disease states at preventative, diagnostic, promotive, and curative levels. Due to the many adverse effects of conventional treatment consisting of synthetic drugs, there is a surge in demand for complementary and alternative therapies, mainly herbal botanicals. With the paucity of empirical evidence on the mechanistic routes of herbal medications used till now, the medical world has had difficulty accepting them. As a result, there has been a surge in interest in deciphering the mechanisms of action of herbal compositions. Our work will highlight the various phytochemicals, such as flavonoids, alkaloids, glycosides, volatile oils, resins, organic acids, amino acids, tannins, proteins, and trace elements polysaccharides present in various plants that can be employed as a treatment option to cure major diseases.