Recent Advances in the Rational Drug Design Based on Multi-target Ligands

Author(s): Ting Yang, Xin Sui, Bing Yu, Youqing Shen, Hailin Cong*

Journal Name: Current Medicinal Chemistry

Volume 27 , Issue 28 , 2020

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Multi-target drugs have gained considerable attention in the last decade owing to their advantages in the treatment of complex diseases and health conditions linked to drug resistance. Single-target drugs, although highly selective, may not necessarily have better efficacy or fewer side effects. Therefore, more attention is being paid to developing drugs that work on multiple targets at the same time, but developing such drugs is a huge challenge for medicinal chemists. Each target must have sufficient activity and have sufficiently characterized pharmacokinetic parameters. Multi-target drugs, which have long been known and effectively used in clinical practice, are briefly discussed in the present article. In addition, in this review, we will discuss the possible applications of multi-target ligands to guide the repositioning of prospective drugs.

Keywords: Multitarget drugs, Alzheimer's disease, Parkinson's disease, cancer, neglected tropical diseases, pharmacokinetic parameters.

Csermely, P.; Agoston, V.; Pongor, S. The efficiency of multi-target drugs: the network approach might help drug design. Trends Pharmacol. Sci., 2005, 26(4), 178-182.
[] [PMID: 15808341]
Chen, Z.F.; Orvig, C.; Liang, H. Multi-Target metal-based anticancer agents. Curr. Top. Med. Chem., 2017, 17(28), 3131-3145.
[] [PMID: 28982336]
Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target directed ligands to combat neurodegenerative diseases. J. Med. Chem., 2008, 51(3), 347-372.
[] [PMID: 18181565]
Kumar, A.; Tiwari, A.; Sharma, A. Changing paradigm from one target one ligand Towards multi-target directed ligand design for key drug targets of Alzheimer Disease: an important role of in silico methods in multi-target directed ligands design. Curr. Neuropharmacol., 2018, 16(6), 726-739.
[] [PMID: 29542413]
Bolognesi, M.L. Polypharmacology in a single drug: multitarget drugs. Curr. Med. Chem., 2013, 20(13), 1639-1645.
[] [PMID: 23410164]
Bolognesi, M.L.; Rosini, M.; Andrisano, V.; Bartolini, M.; Minarini, A.; Tumiatti, V.; Melchiorre, C. MTDL design strategy in the context of Alzheimer’s disease: from lipocrine to memoquin and beyond. Curr. Pharm. Des., 2009, 15(6), 601-613.
[] [PMID: 19199985]
Morphy, R.; Rankovic, Z. Designing multiple ligands - medicinal chemistry strategies and challenges. Curr. Pharm. Des., 2009, 15(6), 587-600.
[] [PMID: 19199984]
Roth, B.L.; Sheffler, D.J.; Kroeze, W.K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov., 2004, 3(4), 353-359.
[] [PMID: 15060530]
Anusuya, S.; Natarajan, J. Multi-targeted therapy for leprosy: insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy. Infect. Genet. Evol., 2012, 12(8), 1899-1910.
[] [PMID: 22981928]
Geldenhuys, W.J.; Van der Schyf, C.J. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr. Med. Chem., 2013, 20(13), 1662-1672.
[] [PMID: 23410161]
Luni, C.; Doyle, F.J. Robust multi-drug therapy design and application to insulin resistance in type 2 diabetes. Int. J. Robust. Nonlin., 2011, 21(15), 1730-1741.
Genin, E.; Hannequin, D.; Wallon, D.; Sleegers, K.; Hiltunen, M.; Combarros, O.; Bullido, M.J.; Engelborghs, S.; De Deyn, P.; Berr, C.; Pasquier, F.; Dubois, B.; Tognoni, G.; Fiévet, N.; Brouwers, N.; Bettens, K.; Arosio, B.; Coto, E.; Del Zompo, M.; Mateo, I.; Epelbaum, J.; Frank-Garcia, A.; Helisalmi, S.; Porcellini, E.; Pilotto, A.; Forti, P.; Ferri, R.; Scarpini, E.; Siciliano, G.; Solfrizzi, V.; Sorbi, S.; Spalletta, G.; Valdivieso, F.; Vepsäläinen, S.; Alvarez, V.; Bosco, P.; Mancuso, M.; Panza, F.; Nacmias, B.; Bossù, P.; Hanon, O.; Piccardi, P.; Annoni, G.; Seripa, D.; Galimberti, D.; Licastro, F.; Soininen, H.; Dartigues, J.F.; Kamboh, M.I.; Van Broeckhoven, C.; Lambert, J.C.; Amouyel, P.; Campion, D. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry, 2011, 16(9), 903-907.
[] [PMID: 21556001]
Bolognesi, M.L.; Matera, R.; Minarini, A.; Rosini, M.; Melchiorre, C. Alzheimer’s disease: new approaches to drug discovery. Curr. Opin. Chem. Biol., 2009, 13(3), 303-308.
[] [PMID: 19467915]
Metcalfe, M.J.; Figueiredo-Pereira, M.E. Relationship between tau pathology and neuroinflammation in Alzheimer’s disease. Mt. Sinai J. Med., 2010, 77(1), 50-58.
[] [PMID: 20101714]
Carpenter, B.D.; Balsis, S.; Otilingam, P.G.; Hanson, P.K.; Gatz, M. The Alzheimer’s Disease Knowledge Scale: development and psychometric properties. Gerontologist, 2009, 49(2), 236-247.
[] [PMID: 19363018]
Barranco-Quintana, J.L.; Allam, M.F.; Del Castillo, A.; Navajas, R.F.C. Alzheimer’s disease risk factors. Rev. Neurol., 2005, 40(10), 613-618.
[PMID: 15926136]
Moreira, P.I.; Zhu, X.; Liu, Q.; Honda, K.; Siedlak, S.L.; Harris, P.L.; Smith, M.A.; Perry, G. Compensatory responses induced by oxidative stress in Alzheimer disease. Biol. Res., 2006, 39(1), 7-13.
[] [PMID: 16629160]
Gong, C.X.; Lidsky, T.; Wegiel, J.; Zuck, L.; Grundke-Iqbal, I.; Iqbal, K. Phosphorylation of microtubule associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J. Biol. Chem., 2000, 275(8), 5535-5544.
[] [PMID: 10681533]
Farber, S.A.; Slack, B.E.; Blusztajn, J.K. Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer’s disease. FASEB J., 2000, 14(14), 2198-2206.
[] [PMID: 11053240]
Pohanka, M. Oxidative stress in Alzheimer disease as a target for therapy. Bratisl. Lek Listy, 2018, 119(9), 535-543.
[] [PMID: 30226062]
Sonnen, J.A.; Larson, E.B.; Gray, S.L.; Wilson, A.; Kohama, S.G.; Crane, P.K.; Breitner, J.C.S.; Montine, T.J. Free radical damage to cerebral cortex in Alzheimer’s disease, microvascular brain injury, and smoking. Ann. Neurol., 2009, 65(2), 226-229.
[] [PMID: 19259965]
Oz, M.; Lorke, D.E.; Yang, K.H.S.; Petroianu, G. On the interaction of β-amyloid peptides and α7-nicotinic acetylcholine receptors in Alzheimer’s disease. Curr. Alzheimer Res., 2013, 10(6), 618-630.
[] [PMID: 23627750]
Suo, W.Z. Accelerating Alzheimer’s pathogenesis by GRK5 deficiency via cholinergic dysfunction. Adv. Alzheimer Dis., 2013, 02(04), 148-160.
Enz, A.; Amstutz, R.; Boddeke, H.; Gmelin, G.; Malanowski, J. Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer’s disease. Prog. Brain Res., 1993, 98, 431-438.
[] [PMID: 8248533]
Whitehouse, P.J. Quality of life: the bridge from the cholinergic basal forebrain to cognitive science and bioethics. J. Alzheimers Dis., 2006, 9(Suppl. 3), 447-453.
[] [PMID: 16914884]
Lane, R.M.; Potkin, S.G.; Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol., 2006, 9(1), 101-124.
[] [PMID: 16083515]
Wang, Y.; Wang, H.; Chen, H.Z. AChE inhibition-based multi-target-directed ligands, a novel pharmacological approach for the symptomatic and disease-modifying therapy of Alzheimer’s disease. Curr. Neuropharmacol., 2016, 14(4), 364-375.
[] [PMID: 26786145]
Melchiorre, C.; Andrisano, V.; Bolognesi, M.L.; Budriesi, R.; Cavalli, A.; Cavrini, V.; Rosini, M.; Tumiatti, V.; Recanatini, M. Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer’s disease. J. Med. Chem., 1998, 41(22), 4186-4189.
[] [PMID: 9784091]
Karran, E.; Mercken, M.; De Strooper, B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov., 2011, 10(9), 698-712.
[] [PMID: 21852788]
Ahmad, W.; Ijaz, B.; Shabbiri, K.; Ahmed, F.; Rehman, S. Oxidative toxicity in diabetes and Alzheimer’s disease: mechanisms behind ROS/ RNS generation. J. Biomed. Sci., 2017, 24(1), 76.
[] [PMID: 28927401]
Bush, A.I. The metal theory of Alzheimer’s disease. J. Alzheimers Dis., 2013, 33(Suppl. 1), S277-S281.
[] [PMID: 22635102]
Shamloo, A.; Asadbegi, M.; Khandan, V.; Amanzadi, A. Designing a new multifunctional peptide for metal chelation and Aβ inhibition. Arch. Biochem. Biophys., 2018, 653, 1-9.
[] [PMID: 29906409]
Pudlo, M.; Luzet, V.; Ismaïli, L.; Tomassoli, I.; Iutzeler, A.; Refouvelet, B. Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer disease. Bioorg. Med. Chem., 2014, 22(8), 2496-2507.
[] [PMID: 24657052]
Luo, Z.; Sheng, J.; Sun, Y.; Lu, C.; Yan, J.; Liu, A.; Luo, H.B.; Huang, L.; Li, X. Synthesis and evaluation of multi-target-directed ligands against Alzheimer’s disease based on the fusion of donepezil and ebselen. J. Med. Chem., 2013, 56(22), 9089-9099.
[] [PMID: 24160297]
Ono, K.; Hasegawa, K.; Naiki, H.; Yamada, M. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J. Neurosci. Res., 2004, 75(6), 742-750.
[] [PMID: 14994335]
Meena, P.; Nemaysh, V.; Khatri, M.; Manral, A.; Luthra, P.M.; Tiwari, M. Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease. Bioorg. Med. Chem., 2015, 23(5), 1135-1148.
[] [PMID: 25624107]
Huang, L.; Miao, H.; Sun, Y.; Meng, F.; Li, X. Discovery of indanone derivatives as multi-target-directed ligands against Alzheimer’s disease. Eur. J. Med. Chem., 2014, 87, 429-439.
[] [PMID: 25282266]
Najafi, Z.; Mahdavi, M.; Saeedi, M.; Karimpour-Razkenari, E.; Asatouri, R.; Vafadarnejad, F.; Moghadam, F.H.; Khanavi, M.; Sharifzadeh, M.; Akbarzadeh, T. Novel tacrine-1,2,3-triazole hybrids: In vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors. Eur. J. Med. Chem., 2017, 125, 1200-1212.
[] [PMID: 27863370]
Najafi, Z.; Mahdavi, M.; Saeedi, M.; Karimpour-Razkenari, E.; Edraki, N.; Sharifzadeh, M.; Khanavi, M.; Akbarzadeh, T. Novel tacrine-coumarin hybrids linked to 1,2,3-triazole as anti-Alzheimer’s compounds: In vitro and in vivo biological evaluation and docking study. Bioorg. Chem., 2019, 83, 303-316.
[] [PMID: 30396115]
Chierrito, T.P.C.; Pedersoli-Mantoani, S.; Roca, C.; Requena, C.; Sebastian-Perez, V.; Castillo, W.O.; Moreira, N.C.S.; Pérez, C.; Sakamoto-Hojo, E.T.; Takahashi, C.S.; Jiménez-Barbero, J.; Cañada, F.J.; Campillo, N.E.; Martinez, A.; Carvalho, I. From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer’s disease. Eur. J. Med. Chem., 2017, 139, 773-791.
[] [PMID: 28863358]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002, 297(5580), 353-356.
[] [PMID: 12130773]
Tang, B.L.; Liou, Y.C. Novel modulators of amyloid-beta precursor protein processing. J. Neurochem., 2007, 100(2), 314-323.
[] [PMID: 17241154]
Yahiaoui, S.; Hamidouche, K.; Ballandonne, C.; Davis, A.; de Oliveira Santos, J.S.; Freret, T.; Boulouard, M.; Rochais, C.; Dallemagne, P. Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2016, 121, 283-293.
[] [PMID: 27266998]
Sarajärvi, T.; Jäntti, M.; Paldanius, K.M.A.; Natunen, T.; Wu, J.C.; Mäkinen, P.; Tarvainen, I.; Tuominen, R.K.; Talman, V.; Hiltunen, M. Protein kinase C -activating isophthalate derivatives mitigate Alzheimer’s disease-related cellular alterations. Neuropharmacology, 2018, 141, 76-88.
[] [PMID: 30138694]
Cacciatore, I.; Marinelli, L.; Fornasari, E.; Cerasa, L.S.; Eusepi, P.; Türkez, H.; Pomilio, C.; Reale, M.; D’Angelo, C.; Costantini, E.; Di Stefano, A. Novel NSAID-derived drugs for the potential treatment of Alzheimer’s disease. Int. J. Mol. Sci., 2016, 17(7) E1035
[] [PMID: 27376271]
Flagmeier, P.; Meisl, G.; Vendruscolo, M.; Knowles, T.P.J.; Dobson, C.M.; Buell, A.K.; Galvagnion, C. Mutations associated with familial Parkinson’s disease alter the initiation and amplification steps of α-synuclein aggregation. Proc. Natl. Acad. Sci. USA, 2016, 113(37), 10328-10333.
[] [PMID: 27573854]
Rolli-Derkinderen, M.; Leclair-Visonneau, L.; Bourreille, A.; Coron, E.; Neunlist, M.; Derkinderen, P. Is Parkinson’s disease a chronic low-grade inflammatory bowel disease? J. Neurol., 2019.
[] [PMID: 30989372]
Pozo Devoto, V.M.; Falzone, T.L. Mitochondrial dynamics in Parkinson’s disease: a role for α-synuclein? Dis. Model. Mech., 2017, 10(9), 1075-1087.
[] [PMID: 28883016]
Guzior, N.; Wieckowska, A.; Panek, D.; Malawska, B. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer’s disease. Curr. Med. Chem., 2015, 22(3), 373-404.
[] [PMID: 25386820]
Haddad, D.; Nakamura, K. Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson’s disease. FEBS Lett., 2015, 589(24 Pt A), 3702-3713.
[] [PMID: 26526613]
Faust, K.; Gehrke, S.; Yang, Y.; Yang, L.; Beal, M.F.; Lu, B. Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson’s disease. BMC Neurosci., 2009, 10, 109.
[] [PMID: 19723328]
Long-Smith, C.M.; Sullivan, A.M.; Nolan, Y.M. The influence of microglia on the pathogenesis of Parkinson’s disease. Prog. Neurobiol., 2009, 89(3), 277-287.
[] [PMID: 19686799]
Ferré, S.; Popoli, P.; Giménez-Llort, L.; Rimondini, R.; Müller, C.E.; Strömberg, I.; Ögren, S.O.; Fuxe, K. Adenosine/dopamine interaction: implications for the treatment of Parkinson’s disease. Parkinsonism Relat. Disord., 2001, 7(3), 235-241.
[] [PMID: 11331192]
Morelli, M.; Di Paolo, T.; Wardas, J.; Calon, F.; Xiao, D.; Schwarzschild, M.A. Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Prog. Neurobiol., 2007, 83(5), 293-309.
[] [PMID: 17826884]
Jenner, P.; Mori, A.; Hauser, R.; Morelli, M.; Fredholm, B.B.; Chen, J.F. Adenosine, adenosine A 2A antagonists, and Parkinson’s disease. Parkinsonism Relat. Disord., 2009, 15(6), 406-413.
[] [PMID: 19446490]
Petzer, J.P.; Castagnoli, N., Jr.; Schwarzschild, M.A.; Chen, J.F.; Van der Schyf, C.J. Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson’s disease. Neurotherapeutics, 2009, 6(1), 141-151.
[] [PMID: 19110205]
Fišar, Z. Drugs related to monoamine oxidase activity. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2016, 69, 112-124.
[] [PMID: 26944656]
Chen, J.F.; Steyn, S.; Staal, R.; Petzer, J.P.; Xu, K.; Van Der Schyf, C.J.; Castagnoli, K.; Sonsalla, P.K.; Castagnoli, N., Jr; Schwarzschild, M.A. 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. J. Biol. Chem., 2002, 277(39), 36040-36044.
[] [PMID: 12130655]
Pretorius, J.; Malan, S.F.; Castagnoli, N., Jr; Bergh, J.J.; Petzer, J.P. Dual inhibition of monoamine oxidase B and antagonism of the adenosine A(2A) receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues. Bioorg. Med. Chem., 2008, 16(18), 8676-8684.
[] [PMID: 18723354]
Stössel, A.; Schlenk, M.; Hinz, S.; Küppers, P.; Heer, J.; Gütschow, M.; Müller, C.E. Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones. J. Med. Chem., 2013, 56(11), 4580-4596.
[] [PMID: 23631427]
Robinson, S.J.; Petzer, J.P.; Terre’Blanche, G.; Petzer, A.; van der Walt, M.M.; Bergh, J.J.; Lourens, A.C. 2-Aminopyrimidines as dual adenosine A1/A2A antagonists. Eur. J. Med. Chem., 2015, 104, 177-188.
[] [PMID: 26462195]
Mori, A. Adenosine A2A receptor antagonists as a novel non-dopaminergic therapy for Parkinson’s disease: A potential mechanism of the antiparkinsonian action. J. Neurol. Sci., 2006, 248(1-2), 319-319.
Müller, W.E.; Eckert, A.; Kurz, C.; Eckert, G.P.; Leuner, K. Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer’s disease--therapeutic aspects. Mol. Neurobiol., 2010, 41(2-3), 159-171.
[] [PMID: 20461558]
Ammal Kaidery, N.; Thomas, B. Current perspective of mitochondrial biology in Parkinson’s disease. Neurochem. Int., 2018, 117, 91-113.
[] [PMID: 29550604]
Biju, K.C.; Evans, R.C.; Shrestha, K.; Carlisle, D.C.B.; Gelfond, J.; Clark, R.A. Methylene blue ameliorates olfactory dysfunction and motor deficits in a chronic MPTP/probenecid mouse model of Parkinson’s disease. Neuroscience, 2018, 380, 111-122.
[] [PMID: 29684508]
Zaitone, S.A.; Abo-Elmatty, D.M.; Elshazly, S.M. Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats. Indian J. Pharmacol., 2012, 44(6), 774-779.
[] [PMID: 23248410]
Tan, W.; Xue-bin, C.; Tian, Z.; Xiao-wu, C.; Pei-pei, H.; Zhi-bin, C.; Bei-sha, T. Effects of simvastatin on the expression of inducible nitric oxide synthase and brain-derived neurotrophic factor in a lipopolysaccharide-induced rat model of Parkinson disease. Int. J. Neurosci., 2016, 126(3), 278-286.
[] [PMID: 26000813]
Kuang, S.; Yang, L.; Rao, Z.; Zhong, Z.; Li, J.; Zhong, H.; Dai, L.; Tang, X. Effects of ginkgo biloba extract on A53T alpha-synuclein transgenic mouse models of Parkinson’s disease. Can. J. Neurol. Sci., 2018, 45(2), 182-187.
[] [PMID: 29506601]
Shirooie, S.; Nabavi, S.F.; Dehpour, A.R.; Belwal, T.; Habtemariam, S.; Argüelles, S.; Sureda, A.; Daglia, M.; Tomczyk, M.; Sobarzo-Sanchez, E.; Xu, S.; Nabavi, S.M. Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration? Pharmacol. Res., 2018, 135, 37-48.
[] [PMID: 29990625]
Yong-Kee, C.J.; Sidorova, E.; Hanif, A.; Perera, G.; Nash, J.E. Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson’s disease. Neurotox. Res., 2012, 21(2), 185-194.
[] [PMID: 21773851]
Almeida, A.S.; Vieira, H.L.A. Role of cell metabolism and mitochondrial function during adult neurogenesis. Neurochem. Res., 2017, 42(6), 1787-1794.
[] [PMID: 28000162]
Giedt, R.J.; Pfeiffer, D.R.; Matzavinos, A.; Kao, C.Y.; Alevriadou, B.R. Mitochondrial dynamics and motility inside living vascular endothelial cells: role of bioenergetics. Ann. Biomed. Eng., 2012, 40(9), 1903-1916.
[] [PMID: 22527011]
Golpich, M.; Amini, E.; Mohamed, Z.; Azman Ali, R.; Mohamed Ibrahim, N.; Ahmadiani, A. Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: pathogenesis and treatment. CNS Neurosci. Ther., 2017, 23(1), 5-22.
[] [PMID: 27873462]
Umeno, A.; Biju, V.; Yoshida, Y. In vivo ROS production and use of oxidative stress-derived biomarkers to detect the onset of diseases such as Alzheimer’s disease, Parkinson’s disease and diabetes. Free Radic. Res., 2017, 51(4), 413-427.
[] [PMID: 28372523]
Yue, P.; Gao, L.; Wang, X.; Ding, X.; Teng, J. Pretreatment of glial cell-derived neurotrophic factor and geranylgeranylacetone ameliorates brain injury in Parkinson’s disease by its anti-apoptotic and anti-oxidative property. J. Cell. Biochem., 2018, 119(7), 5491-5502.
[] [PMID: 29377238]
Nomura, D.K.; Dix, M.M.; Cravatt, B.F. Activity-based protein profiling for biochemical pathway discovery in cancer. Nat. Rev. Cancer, 2010, 10(9), 630-638.
[] [PMID: 20703252]
Gou, Y.; Zhang, Z.; Li, D.; Zhao, L.; Cai, M.; Sun, Z.; Li, Y.; Zhang, Y.; Khan, H.; Sun, H.; Wang, T.; Liang, H.; Yang, F. HSA-based multi-target combination therapy: regulating drugs’ release from HSA and overcoming single drug resistance in a breast cancer model. Drug Deliv., 2018, 25(1), 321-329.
[] [PMID: 29350051]
Jin, H.; Dan, H.G.; Rao, G.W. Research progress in quinazoline derivatives as multi-target tyrosine kinase inhibitors. Heterocycl. Commun., 2018, 24(1), 1-10.
Gossage, L.; Eisen, T. Targeting multiple kinase pathways: a change in paradigm. Clin. Cancer Res., 2010, 16(7), 1973-1978.
[] [PMID: 20215532]
Kranenburg, O.; Emmink, B.L.; Knol, J.; van Houdt, W.J.; Rinkes, I.H.M.B.; Jimenez, C.R. Proteomics in studying cancer stem cell biology. Expert Rev. Proteomics, 2012, 9(3), 325-336.
[] [PMID: 22809210]
Raevsky, O.A.; Mukhametov, A.; Grigorev, V.Y.; Ustyugov, A.; Tsay, S.C.; Jih-Ru Hwu, R.; Yarla, N.S.; Tarasov, V.V.; Aliev, G.; Bachurin, S.O. Applications of multi-target computer-aided methodologies in molecular design of CNS drugs. Curr. Med. Chem., 2018, 25(39), 5293-5314.
[] [PMID: 28933295]
Okura, R.; Yoshioka, H.; Yoshioka, M.; Hiromasa, K.; Nishio, D.; Nakamura, M. Expression of AID in malignant melanoma with BRAF(V600E) mutation. Exp. Dermatol., 2014, 23(5), 347-348.
[] [PMID: 24684646]
Poulikakos, P.I.; Zhang, C.; Bollag, G.; Shokat, K.M.; Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 2010, 464(7287), 427-430.
[] [PMID: 20179705]
Wada, M.; Horinaka, M.; Yamazaki, T.; Katoh, N.; Sakai, T. The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells. PLoS One, 2014, 9(11) e113217
[] [PMID: 25422890]
Den, R.B.; Lu, B. Heat shock protein 90 inhibition: rationale and clinical potential. Ther. Adv. Med. Oncol., 2012, 4(4), 211-218.
[] [PMID: 22754594]
Rasouliha, B.H.; Zhou, Y.S.; Chen, W.N. iTRAQ-coupled 2D LC-MS/MS analysis of protein profile in MCF-7 human breast cancer cells incubated with doxorubicin: Potential role of heat shock protein 90. J. Med. Imag. Health. In., 2011, 1(2), 193-195.
Moulick, K.; Ahn, J.H.; Zong, H.; Rodina, A.; Cerchietti, L.; Gomes DaGama, E.M.; Caldas-Lopes, E.; Beebe, K.; Perna, F.; Hatzi, K.; Vu, L.P.; Zhao, X.; Zatorska, D.; Taldone, T.; Smith-Jones, P.; Alpaugh, M.; Gross, S.S.; Pillarsetty, N.; Ku, T.; Lewis, J.S.; Larson, S.M.; Levine, R.; Erdjument-Bromage, H.; Guzman, M.L.; Nimer, S.D.; Melnick, A.; Neckers, L.; Chiosis, G. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat. Chem. Biol., 2011, 7(11), 818-826.
[] [PMID: 21946277]
Zhang, Q.; Zhai, S.; Li, L.; Li, X.; Zhou, H.; Liu, A.; Su, G.; Mu, Q.; Du, Y.; Yan, B. Anti-tumor selectivity of a novel tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models. Biochem. Pharmacol., 2013, 86(3), 351-360.
[] [PMID: 23743233]
Detmar, M. Tumor angiogenesis. J. Investig. Dermatol. Symp. Proc., 2000, 5(1), 20-23.
[] [PMID: 11147670]
Di Cesare, E.; Verrico, A.; Miele, A.; Giubettini, M.; Rovella, P.; Coluccia, A.; Famiglini, V.; La Regina, G.; Cundari, E.; Silvestri, R.; Lavia, P. Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules. Oncotarget, 2017, 8(12), 19738-19759.
[] [PMID: 28160569]
Chekler, E.L.P.; Kiselyov, A.S.; Ouyang, X.; Chen, X.; Pattaropong, V.; Wang, Y.; Tuma, M.C.; Doody, J.F. Discovery of dual VEGFR-2 and tubulin inhibitors with in vivo efficacy. ACS Med. Chem. Lett., 2010, 1(9), 488-492.
[] [PMID: 24900236]
Li, X.; Wu, C.; Lin, X.; Cai, X.; Liu, L.; Luo, G.; You, Q.; Xiang, H. Synthesis and biological evaluation of 3-aryl-quinolin derivatives as anti-breast cancer agents targeting ERα and VEGFR-2. Eur. J. Med. Chem., 2019, 161, 445-455.
[] [PMID: 30384047]
Campo, L.; Mathew, M.; Breuer, E.K.; Small, W. The role of TACC3 in the progression from ductal carcinoma in situ to invasive breast cancer. Cancer Res., 2017, 77.
de Oliveira Viana, J.; Ishiki, H.M.; Scotti, M.T.; Scotti, L. Multi-target antitubercular drugs. Curr. Top. Med. Chem., 2018, 18(9), 750-758.
[] [PMID: 29807515]
Ghazaei, C. Mycobacterium tuberculosis and lipids: Insights into molecular mechanisms from persistence to virulence. J. Res. Med. Sci., 2018, 23, 63.
[] [PMID: 30181745]
Saravanan, P.; Patra, S. Discovery of potential dual inhibitors against lipases Rv0183 and Rv3802c for tuberculosis therapeutics. Lett. Drug Des. Discov., 2016, 13(2), 185-195.
Watts, C. Neglected tropical diseases: a DFID perspective. Plos. Neglect. Trop. D, 2017, 11(4) e0005492.
[] [PMID: 28426666]
Molyneux, D.H. Neglected tropical diseases: now more than just ‘other diseases’--the post-2015 agenda. Int. Health, 2014, 6(3), 172-180.
[] [PMID: 24969646]
Coelho, G.S.; Andrade, J.S.; Xavier, V.F.; Sales Junior, P.A.; Rodrigues de Araujo, B.C.; Fonseca, K.D.S.; Caetano, M.S.; Murta, S.M.F.; Vieira, P.M.; Carneiro, C.M.; Taylor, J.G. Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi. Chem. Biol. Drug Des., 2019, 93(3), 337-350.
[] [PMID: 30362274]
Aguilera, E.; Varela, J.; Birriel, E.; Serna, E.; Torres, S.; Yaluff, G.; de Bilbao, N.V.; Aguirre-López, B.; Cabrera, N.; Díaz Mazariegos, S.; de Gómez-Puyou, M.T.; Gómez-Puyou, A.; Pérez-Montfort, R.; Minini, L.; Merlino, A.; Cerecetto, H.; González, M.; Alvarez, G. Potent and selective inhibitors of trypanosoma cruzi triosephosphate isomerase with concomitant inhibition of cruzipain: inhibition of parasite growth through multitarget activity. Chem. Med. Chem., 2016, 11(12), 1328-1338.
[] [PMID: 26492824]
Belluti, F.; Uliassi, E.; Veronesi, G.; Bergamini, C.; Kaiser, M.; Brun, R.; Viola, A.; Fato, R.; Michels, P.A.M.; Krauth-Siegel, R.L.; Cavalli, A.; Bolognesi, M.L. Toward the development of dual-targeted glyceraldehyde-3-phosphate dehydrogenase/trypanothione reductase inhibitors against Trypanosoma brucei and Trypanosoma cruzi. ChemMedChem, 2014, 9(2), 371-382.
[] [PMID: 24403089]
Stolp, Z.D.; Smurthwaite, C.A.; Reed, C.; Williams, W.; Dharmawan, A.; Djaballah, H.; Wolkowicz, R. A multiplexed cell-based assay for the identification of modulators of pre-membrane processing as a target against dengue virus. J. Biomol. Screen., 2015, 20(5), 616-626.
[] [PMID: 25724189]
Sankarasubramanian, J.; Pavithra, K.B.; Kavitha, B. Identification of potent inhibitor for RNA dependent RNA polymerase (RDRP) of dengue virus serotype-3: A molecular docking study. J. Appl. Bioinforma. Comput. Biol., 2015, 04(01)
Mustafa, M.S.; Rasotgi, V.; Jain, S.; Gupta, V. Discovery of fifth serotype of dengue virus (DENV-5): A new public health dilemma in dengue control. Med. J. Armed Forces India, 2015, 71(1), 67-70.
[] [PMID: 25609867]
Qamar, M.T.U.; Arooj, M.; Rabbia, N.; Amna, A.; Tabeer, F.; Tehreem, J.; Zubair, A.; Usman Ali, A.J.B. Molecular docking based screening of plant flavonoids as Dengue NS1 inhibitors. Bioinformation, 2014, 10(7), 460-465.
[] [PMID: 25187688]
Senthilvel, P.; Lavanya, P.; Kumar, K.M.; Swetha, R.; Anitha, P.; Bag, S.; Sarveswari, S.; Vijayakumar, V.; Ramaiah, S.; Anbarasu, A. Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents Dengue 2 viral assembly. Bioinformation, 2013, 9(18), 889-895.
[] [PMID: 24307765]
de Sousa, L.R.F.; Wu, H.; Nebo, L.; Fernandes, J.B.; da Silva, M.F.D.F.; Kiefer, W.; Kanitz, M.; Bodem, J.; Diederich, W.E.; Schirmeister, T.; Vieira, P.C. Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: inhibition kinetics and docking studies. Bioorg. Med. Chem., 2015, 23(3), 466-470.
[] [PMID: 25564380]
Ye, H.; Ye, L.; Kang, H.; Zhang, D.; Tao, L.; Tang, K.; Liu, X.; Zhu, R.; Liu, Q.; Chen, Y.Z.; Li, Y.; Cao, Z. HIT: linking herbal active ingredients to targets. Nucleic Acids Res., 2011, 39(Database issue), D1055-D1059.
[] [PMID: 21097881]

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Year: 2020
Page: [4720 - 4740]
Pages: 21
DOI: 10.2174/0929867327666200102120652
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