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Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Mini-Review Article

Growing Preferences towards Analog-based Drug Discovery

Author(s): Mehak Dangi, Alka Khichi, Ritu Jakhar and Anil K. Chhillar*

Volume 22, Issue 8, 2021

Published on: 08 September, 2020

Page: [1030 - 1045] Pages: 16

DOI: 10.2174/1389201021666200908121409

Price: $65


Background: The major concern of today's time is the developing resistance in most of the clinically derived pathogenic micro-organisms for available drugs through several mechanisms. Therefore, there is a dire need to develop novel molecules with drug-like properties that can be effective against the otherwise resistant micro-organisms.

Methods: New drugs can be developed using several methods like structure-based drug design, ligandbased drug design, or by developing analogs of the available drugs to further improve their effects. However, the smartness is to opt for the techniques that have comparatively less expenditure, lower failure rates, and faster discovery rates.

Results: Analog-Based Drug Design (ABDD) is one such technique that researchers worldwide are opting to develop new drug-like molecules with comparatively lower market values. They start by first designing the analogs sharing structural and pharmacological similarities to the existing drugs. This method embarks on scaffold structures of available drugs already approved by the clinical trials, but are left ineffective because of resistance developed by the pathogens.

Conclusion: In this review, we have discussed some recent examples of anti-fungal and anti-bacterial (antimicrobial) drugs that were designed based on the ABDD technique. Also, we have tried to focus on the in silico tools and techniques that can contribute to the designing and computational screening of the analogs, so that these can be further considered for in vitro screening to validate their better biological activities against the pathogens with comparatively reduced rates of failure.

Keywords: Derivatives, analogs, drug discovery, antimicrobial, in silico, pathogens.

Graphical Abstract
Wang, Y.; Xu, K.; Bai, G.; Huang, L.; Wu, Q.; Pan, W.; Yu, S. Synthesis and antifungal activity of novel triazole compounds containing piperazine moiety. Molecules, 2014, 19(8), 11333-11340.
[] [PMID: 25090121]
Wermuth, C.G. Similarity in drug: Reflections on analogue design. Drug Discov. Today, 2006, 11, 1359-6446.
Dickinson, R.P.; Bell, A.S.; Hitchcock, C.A.; Narayanaswami, S.; Ray, S.J.D.; Richardson, K.; Troke, P.F. Novel antifungal 2- aryl-1-(1h-1,2,4- triazole-1-yl) butan-2-ol derivatives with high activity against aspergillus. Bioorg. Med. Chem. Lett., 1996, 6, 2031-2036.
Upadhayaya, R.S.; Jain, S.; Sinha, N.; Kishore, N.; Chandra, R.; Arora, S.K. Synthesis of novel substituted tetrazoles having antifungal activity. Eur. J. Med. Chem., 2004, 39(7), 579-592.
[] [PMID: 15236838]
Nam, N.H.; Sardari, S.; Selecky, M.; Parang, K. Carboxylic acid and phosphate ester derivatives of fluconazole: Synthesis and antifungal activities. Bioorg. Med. Chem., 2004, 12(23), 6255-6269.
[] [PMID: 15519168]
Fasugba, O.; Gardner, A.; Mitchell, B.G.; Mnatzaganian, G. Ciprofloxacin resistance in community- and hospital-acquired Escherichia coli urinary tract infections: A systematic review and meta-analysis of observational studies. BMC Infect. Dis., 2015, 15, 545.
[] [PMID: 26607324]
Reis, A.C.; Santos, S.R.; Souza, S.C.; Saldanha, M.G.; Pitanga, T.N.; Oliveira, R.R. Ciprofloxacin resistance pattern among bacteria isolated from patients with community-acquired urinary tract infection. Rev. Inst. Med. Trop. São Paulo, 2016, 58, 53.
[] [PMID: 27410913]
Mulder, M.; Kiefte-de Jong, J.C.; Goessens, W.H.; de Visser, H.; Hofman, A.; Stricker, B.H.; Verbon, A. Risk factors for resistance to ciprofloxacin in community-acquired urinary tract infections due to Escherichia coli in an elderly population. J. Antimicrob. Chemother., 2017, 72(1), 281-289.
[] [PMID: 27655855]
Birkett, D.; Brøsen, K.; Cascorbi, I.; Gustafsson, L.L.; Maxwell, S.; Rago, L.; Rawlins, M.; Reidenberg, M.; Sjöqvist, F.; Smith, T.; Thuerman, P.; Walubo, A.; Orme, M.; Sjöqvist, F. Clinical pharmacology in research, teaching and health care: Considerations by IUPHAR, the International Union of Basic and Clinical Pharmacology. Basic Clin. Pharmacol. Toxicol., 2010, 107(1), 531-559.
[] [PMID: 20590536]
Eto, H.; Kaneko, Y.; Sakamoto, T. New antifungal 1,2,4-triazoles with difluoro(heteroaryl)methyl moiety. Chem. Pharm. Bull. (Tokyo), 2000, 48(7), 982-990.
[] [PMID: 10923827]
Porea, V.S.; Ahera, N.G.; Kumar, M.; Shukla, P.K. Design and synthesis of fluconazole/bile acid conjugate using click reaction. Tetrahedron, 2006, 62, 11178-11186.
Calderone, R.; Sun, N.; Gay-Andrieu, F.; Groutas, W.; Weerawarna, P.; Prasad, S.; Alex, D.; Li, D. Antifungal drug discovery: The process and outcomes. Future Microbiol., 2014, 9(6), 791-805.
[] [PMID: 25046525]
Lebouvier, N.; Pagniez, F.; Duflos, M.; Le Pape, P.; Na, Y.M.; Le Baut, G.; Le Borgne, M. Synthesis and antifungal activities of new fluconazole analogues with azaheterocycle moiety. Bioorg. Med. Chem. Lett., 2007, 17(13), 3686-3689.
[] [PMID: 17482460]
Omar, K.; Geronikaki, A.; Zoumpoulakis, P.; Camoutsis, C.; Soković, M.; Cirić, A.; Glamoclija, J. Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs. Bioorg. Med. Chem., 2010, 18(1), 426-432.
[] [PMID: 19914077]
Zhang, Y.Y.; Mi, J.L.; Zhou, C.H.; Zhou, X.D. Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities. Eur. J. Med. Chem., 2011, 46(9), 4391-4402.
[] [PMID: 21794961]
Shrestha, S.K.; Fosso, M.Y.; Green, K.D.; Garneau-Tsodikova, S. Amphiphilic tobramycin analogues as antibacterial and antifungal agents. Antimicrob. Agents Chemother., 2015, 59(8), 4861-4869.
[] [PMID: 26033722]
Herzog, I.M.; Green, K.D.; Berkov-Zrihen, Y.; Feldman, M.; Vidavski, R.R.; Eldar-Boock, A.; Satchi-Fainaro, R.; Eldar, A.; Garneau-Tsodikova, S.; Fridman, M. 6′'-Thioether tobramycin analogues: Towards selective targeting of bacterial membranes. Angew. Chem. Int. Ed. Engl., 2012, 51(23), 5652-5656.
[] [PMID: 22499286]
Ngo, H.X.; Shrestha, S.K.; Garneau-Tsodikova, S. Identification of ebsulfur analogues with broad-spectrum antifungal activity. ChemMedChem, 2016, 11(14), 1507-1516.
[] [PMID: 27334363]
Huerta, A.Z.; Castaneda, D.D.C.; Renedo, J.B.; Zeron, H.M.; Fernandez, R.C.M.; Romero, S.P.; Rodriguez, M.M.; Uribe, B.A.F.; Rivas, N.G.; Yanez, E.C. Synthesis and in vitro biological evaluation of 1,3-bis-(1,2,3-triazol1-yl)-propan-2-ol derivatives as antifungal compounds〉uconazole analogues. Med. Chem. Res., 2019, 28, 571-579.
Cruz, K.S.; Lima, E.S.; Silva, M.D.J.A.D.; Souza, E.S.D.; Montoia, A.; Pohlit, A.M.; Souza, J.V.B.D. Screening and antifungal activity of a β -carboline derivative against Cryptococcus neoformans and C. gattii. Int. J. Microbiol. Res., 2019, Article ID 7157845..
Bezzerri, V.; Avitabile, C.; Dechecchi, M.C.; Lampronti, I.; Borgatti, M.; Montagner, G.; Cabrini, G.; Gambari, R.; Romanelli, A. Antibacterial and anti-inflammatory activity of a temporin B peptide analogue on an in vitro model of cystic fibrosis. J. Pept. Sci., 2014, 20, 822-830.
Amoh, T.; Murakami, K.; Kariyama, R.; Hori, K.; Viducic, D.; Hirota, K.; Igarashi, J.; Suga, H.; Parsek, M.R.; Kumon, H.; Miyake, Y. Effects of an auto inducer analogue on antibiotic tolerance in Pseudomonas aeruginosa. J. Antimicrob. Chemother., 2017, 72(8), 2230-2240.
[] [PMID: 28510695]
Kim, M.K.; Kang, H.K.; Ko, S.J.; Hong, M.J.; Bang, J.K.; Seo, C.H.; Park, Y. Mechanisms driving the antibacterial and antibiofilm properties of Hp1404 and its analogue peptides against multidrug-resistant Pseudomonas aeruginosa. Sci. Rep., 2018, 8(1), 1763.
[] [PMID: 29379033]
Teske, K.A.; Dash, R.C.; Morel, S.R.; Chau, L.Q.; Wechsler-Reya, R.J.; Hadden, M.K. Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors. Eur. J. Med. Chem., 2019, 163, 320-332.
[] [PMID: 30529635]
Mushtaq, G.; Greig, N.H.; Khan, J.A.; Kamal, M.A. Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol. Disord. Drug Targets, 2014, 13(8), 1432-1439.
[] [PMID: 25345511]
Gurjar, A.S.; Darekar, M.N.; Yeong, K.Y.; Ooi, L. In silico studies, synthesis and pharmacological evaluation to explore multi-targeted approach for imidazole analogues as potential cholinesterase inhibitors with neuroprotective role for Alzheimer’s disease. Bioorg. Med. Chem., 2018, 26(8), 1511-1522.
[] [PMID: 29429576]
Ravichandiran, P.; Sheet, S.; Premnath, D.; Kim, A.R.; Yoo, D.J. 1,4-naphthoquinone analogues: Potent antibacterial agents and mode of action evaluation. Molecules, 2019, 24(7), 1437.
[] [PMID: 30979056]
Ravichandiran, P.; Subramaniyan, S.A.; Kim, S.Y.; Kim, J.S.; Park, B.H.; Shim, K.S.; Yoo, D.J. Synthesis and anticancer evaluation of novel 1,4-naphthoquinone derivatives containing a phenylamino-sulfanyl moiety. ChemMedChem, 2019, 14(5), 532-544.
[] [PMID: 30600915]
Deng, Y.; Weng, X.; Li, Y.; Su, M.; Wen, Z.; Ji, X.; Ren, N.; Shen, B.; Duan, Y.; Huang, Y. Late-stage functionalization of platensimycin leading to multiple analogues with improved antibacterial activity in vitro and in vivo. J. Med. Chem., 2019, 62(14), 6682-6693.
[] [PMID: 31265289]
Levin-Reisman, I.; Ronin, I.; Gefen, O.; Braniss, I.; Shoresh, N.; Balaban, N.Q. Antibiotic tolerance facilitates the evolution of resistance. Science, 2017, 355(6327), 826-830.
[] [PMID: 28183996]
Sprenger, M.; Fukuda, K. Antimicrobial resistance. New mechanisms, new worries. Science, 2016, 351(6279), 1263-1264.
[] [PMID: 26989235]
Brown, E.D.; Wright, G.D. Antibacterial drug discovery in the resistance era. Nature, 2016, 529(7586), 336-343.
[] [PMID: 26791724]
Silver, L.L. Challenges of antibacterial discovery. Clin. Microbiol. Rev., 2011, 24(1), 71-109.
[] [PMID: 21233508]
Fang, K.C.; Chen, Y.L.; Sheu, J.Y.; Wang, T.C.; Tzeng, C.C. Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives. J. Med. Chem., 2000, 43(20), 3809-3812.
[] [PMID: 11020298]
Bisacchi, G.S. Origins of the quinolone class of antibacterials: An expanded “discovery story”. J. Med. Chem., 2015, 58(12), 4874-4882.
[] [PMID: 25738967]
Wang, L.L.; Battini, N.; Bheemanaboina, R.R.Y.; Zhang, S.L.; Zhou, C.H. Design and synthesis of aminothiazolyl norfloxacin analogues as potential antimicrobial agents and their biological evaluation. Eur. J. Med. Chem., 2019, 167, 105-123.
[] [PMID: 30769240]
Abouelhassan, Y.; Zhang, P.; Ding, Y.; Huigens, I.R.W. Rapid kill assessment of an N-arylated NH125 analogue against drug-resistant microorganisms. MedChemComm, 2019, 10(5), 712-716.
[] [PMID: 31191861]
Blaser, A.; Sutherland, H.S.; Tong, A.S.T.; Choi, P.J.; Conole, D.; Franzblau, S.G.; Cooper, C.B.; Upton, A.M.; Lotlikar, M.; Denny, W.A.; Palmer, B.D. Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline. Bioorg. Med. Chem., 2019, 27(7), 1283-1291.
[] [PMID: 30792104]
Guillemont, J.; Meyer, C.; Poncelet, A.; Bourdrez, X.; Andries, K. Diarylquinolines, synthesis pathways and quantitative structure-activity relationship studies leading to the discovery of TMC207. Future Med. Chem., 2011, 3(11), 1345-1360.
[] [PMID: 21879841]
Tong, A.S.T.; Choi, P.J.; Blaser, A.; Sutherland, H.S.; Tsang, S.K.Y.; Guillemont, J.; Motte, M.; Cooper, C.B.; Andries, K.; Van den Broeck, W.; Franzblau, S.G.; Upton, A.M.; Denny, W.A.; Palmer, B.D.; Conole, D. 6-Cyano analogues of bedaquiline as less lipophilic and potentially saferdiaryl quinolones for tuberculosis. ACS Med. Chem. Lett., 2017, 8(10), 1019-1024.
[] [PMID: 29057044]
Collin, F.; Karkare, S.; Maxwell, A. Exploiting bacterial DNA gyrase as a drug target: Current state and perspectives. Appl. Microbiol. Biotechnol., 2011, 92(3), 479-497.
[] [PMID: 21904817]
Emmerson, A.M.; Jones, A.M. The quinolones: Decades of development and use. J. Antimicrob. Chemother., 2003, 51(Suppl. 1), 13-20.
[] [PMID: 12702699]
King, D.E.; Malone, R.; Lilley, S.H. New classification and update on the quinolone antibiotics. Am. Fam. Physician, 2000, 61(9), 2741-2748.
[PMID: 10821154]
Oliphant, C.M.; Green, G.M. Quinolones: A comprehensive review. Am. Fam. Physician, 2002, 65(3), 455-464.
[PMID: 11858629]
Ping, B.; Zhu, Y.; Gao, Y.; Yue, C.; Wu, B. Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: A systematic review and meta-analysis. Ann. Hematol., 2013, 92(6), 831-839.
[] [PMID: 23455400]
Vardanyan, R.; Hruby, V. Antipsychotics. Synthesis of Best-Seller Drugs. Elsevier B., 2016, V, 87-110.
Slater, J.W.; Zechnich, A.D.; Haxby, D.G. Second-generation antihistamines: A comparative review. Drugs, 1999, 57(1), 31-47.
[] [PMID: 9951950]
Benhamou, Y.; Tubiana, R.; Thibault, V. Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus. N. Engl. J. Med., 2003, 348(2), 177-178.
[] [PMID: 12519935]
Ray, A.S.; Fordyce, M.W.; Hitchcock, M.J. Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res., 2016, 125, 63-70.
[] [PMID: 26640223]
Huang, Y.S.; Chang, S.Y.; Sheng, W.H.; Sun, H.Y.; Lee, K.Y.; Chuang, Y.C.; Su, Y.C.; Liu, W.C.; Hung, C.C.; Chang, S.C. Virological response to tenofovirdisoproxilfumarate in HIV-positive patients with lamivudine-resistant hepatitis B virus coinfection in an area hyperendemic for hepatitis B virus infection. PLoS One, 2016, 11(12), e0169228.
[] [PMID: 28033344]
Lam, Y.F.; Seto, W.K.; Wong, D.; Cheung, K.S.; Fung, J.; Mak, L.Y.; Yuen, J.; Chong, C.K.; Lai, C.L.; Yuen, M.F. Seven-year treatment outcome of entecavir in a real-world cohort: Effects on clinical parameters, HBsAg and HBcrAg levels. Clin. Transl. Gastroenterol., 2017, 8(10), e125.
[] [PMID: 29072673]
Stedman, C. Sofosbuvir, a NS5B polymerase inhibitor in the treatment of hepatitis C: A review of its clinical potential. Therap. Adv. Gastroenterol., 2014, 7(3), 131-140.
[] [PMID: 24790644]
De Clercq, E.; Holý, A. Acyclic nucleoside phosphonates: A key class of antiviral drugs. Nat. Rev. Drug Discov., 2005, 4(11), 928-940.
[] [PMID: 16264436]
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury.
Ferreira, L.G.; Dos Santos, R.N.; Oliva, G.; Andricopulo, A.D. Molecular docking and structure-based drug design strategies. Molecules, 2015, 20(7), 13384-13421.
[] [PMID: 26205061]
Arrowsmith, J. Trial watch: Phase III and submission failures: 2007-2010. Nat. Rev. Drug Discov., 2011, 10(2), 87.
[] [PMID: 21283095]
Arrowsmith, J.; Miller, P. Trial watch: Phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug Discov., 2013, 12(8), 569.
[] [PMID: 23903212]
Liu, T.; Lu, D.; Zhang, H.; Zheng, M.; Yang, H.; Xu, Y.; Luo, C.; Zhu, W.; Yu, K.; Jiang, H. Applying high-performance computing in drug discovery and molecular simulation. Natl. Sci. Rev., 2016, 3(1), 49-63.
[] [PMID: 32288960]
Wasko, M.J.; Pellegrene, K.A.; Madura, J.D.; Surratt, C.K. A role for fragment-based drug designing developing novel lead compounds for central nervous system targets. Front. Neurol., 2015, 6, 1-11.
Wadood, A. In silico drug design: An approach which revolutionarised the drug discovery process. OA Drug Design Deliv., 2013, 1(1), 3.
Bernard, D.; Coop, A. MacKerell, A.D. Jr. Computer-aided drug design: Structure-activity relationships of delta opioid ligands. Drug Des Rev., 2005, 2, 277-291.
Chothia, C.; Lesk, A.M. The relation between the divergence of sequence and structure in proteins. EMBO J., 1986, 5(4), 823-826.
[] [PMID: 3709526]
Walters, W.P.; Stahl, M.T.; Murcko, M.A. Virtual screening – an overview. Drug Discov. Today, 1998, 3(4), 160-178.
Bohacek, R.S.; McMartin, C.; Guida, W.C. The art and practice of structure-based drug design: A molecular modeling perspective. Med. Res. Rev., 1996, 16(1), 3-50.
[<3:AID-MED1>3.0.CO;2-6] [PMID: 8788213]
Kövesdi, I.; Dominguez-Rodriguez, M.F.; Orfi, L.; Náray-Szabó, G.; Varró, A.; Papp, J.G.; Mátyus, P. Application of neural networks in structure-activity relationships. Med. Res. Rev., 1999, 19(3), 249-269.
[<249:AID-MED4>3.0.CO;2-0] [PMID: 10232652]
Kennedy, T. Managing the drug discovery/development interface. Drug Discov. Today, 1997, 2, 436-444.
van de Waterbeemd, H. High-throughput and in silico techniques in drug metabolism and pharmacokinetics. Curr. Opin. Drug Discov. Devel., 2002, 5(1), 33-43.
[PMID: 11865671]
Lesk, A.J.M. Introduction to bioinformatics; Oxford University press inc: New York, 2002.
Perdo, H.L. A systematic review on CADD: Docking and Scoring; JMPI, 2010, pp. 47-51.
Wadood, A.; Ahmed, N.; Shah, L.; Ahmad, A.; Hassan, H.; Shams, S. In silico drug design: An approach which revolutionarised the drug discovery process. OA Drug Design & Delivery, 2013, 1(1), 3.
Sliwoski, G.; Kothiwale, S.; Meiler, J.; Lowe, E.W., Jr Computational methods in drug discovery. Pharmacol. Rev., 2013, 66(1), 334-395.
[] [PMID: 24381236]
Kimko, H.; Pinheiro, J. Model-based clinical drug development in the past, present and future: A commentary. Br. J. Clin. Pharmacol., 2015, 79(1), 108-116.
[] [PMID: 24527997]
Gill, S.K.; Christopher, A.F.; Gupta, V.; Bansal, P. Emerging role of bioinformatics tools and software in evolution of clinical research. Perspect. Clin. Res., 2016, 7(3), 115-122.
[] [PMID: 27453827]
Wong, C.H.; Siah, K.W.; Lo, A.W. Estimation of clinical trial success rates and related parameters. Biostatistics, 2019, 20(2), 273-286.
[] [PMID: 29394327]

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