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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

Bioinformatics Paradigms in Drug Discovery and Drug Development

Author(s): Ravinder Sharma, Gunpreet Kaur, Parveen Bansal, Viney Chawla and Vikas Gupta*

Volume 23, Issue 7, 2023

Published on: 18 January, 2023

Page: [579 - 588] Pages: 10

DOI: 10.2174/1568026623666221229113456

Price: $65

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Abstract

Despite breakthroughs in medical sciences, drug development remains a timeconsuming, expensive, challenging, and inefficient process with a high failure rate for novel therapeutic discoveries. Bioinformatics analysis can speed up drug target identification, drug candidate screening, and refining, but it can also help characterise adverse effects and anticipate drug resistance. Integrated genomics, proteomics, and bioinformatics have resulted in potent new tactics for resolving numerous biochemical problems and establishing new methodologies that result in new biomedical products. As a result, a new research trend emerged to demonstrate the mechanism of therapeutic action, forecast drug resistance, and uncover biomarkers for various disorders. The development of new medications is a complicated procedure. There are two basic approaches to drug design: ligand-based drug design and structure-based drug design. The study of protein structure and function was essential for drug development. Current techniques based on combinatorial approaches such as proteomics, genomics, bioinformatics, molecular docking, and mass spectrometry were applied. This article provides an overview of the combinatorial techniques of proteomics, genomics, and bioinformatics that aid in understanding the drug-creation process.

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[1]
Baldi, A. Computational approaches for drug design and discovery: An overview. Sys. Rev. Pharm., 2010, 1(1), 99-105.
[2]
Erhardt, P. Drug Discovery. In: Pharmacology: Principles and Practice; Hacker, M.; Messer, W.S.; Bachmann, K.A., Eds.; Academic Press: USA, 2009; pp. 475-560.
[http://dx.doi.org/10.1016/B978-0-12-369521-5.00019-1]
[3]
Zhou, S.F.; Zhong, W.Z. Drug design and discovery: Principles and applications. Molecules, 2017, 22(2), 279-285.
[http://dx.doi.org/10.3390/molecules22020279] [PMID: 28208821]
[4]
Leelananda, S.P.; Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem., 2016, 12, 2694-2718.
[http://dx.doi.org/10.3762/bjoc.12.267] [PMID: 28144341]
[5]
Marinou, M.; Platis, D.; Ataya, F.S.; Chronopoulou, E.; Vlachakis, D.; Labrou, N.E. Structure-based design and application of a nucleotide coenzyme mimetic ligand: Application to the affinity purification of nucleotide dependent enzymes. J. Chromatogr. A, 2018, 1535, 88-100.
[http://dx.doi.org/10.1016/j.chroma.2018.01.009] [PMID: 29331223]
[6]
Śledź, P.; Caflisch, A. Protein structure-based drug design: From docking to molecular dynamics. Curr. Opin. Struct. Biol., 2018, 48, 93-102.
[http://dx.doi.org/10.1016/j.sbi.2017.10.010] [PMID: 29149726]
[7]
Klebe, G. Recent developments in structure-based drug design. J. Mol. Med. (Berl.), 2000, 78(5), 269-281.
[http://dx.doi.org/10.1007/s001090000084] [PMID: 10954199]
[8]
Fogel, D.B. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp. Clin. Trials Commun., 2018, 11, 156-164.
[http://dx.doi.org/10.1016/j.conctc.2018.08.001] [PMID: 30112460]
[9]
Tanoli, Z.; Alam, Z.; Vähä-Koskela, M.; Ravikumar, B.; Malyutina, A.; Jaiswal, A.; Tang, J.; Wennerberg, K.; Aittokallio, T. Drug Target Commons 2.0: A community platform for systematic analysis of drug-target interaction profiles. Database (Oxford), 2018, 2018, 1-13.
[http://dx.doi.org/10.1093/database/bay083] [PMID: 30219839]
[10]
Koscielny, G.; An, P.; Carvalho-Silva, D.; Cham, J.A.; Fumis, L.; Gasparyan, R.; Hasan, S.; Karamanis, N.; Maguire, M.; Papa, E.; Pierleoni, A.; Pignatelli, M.; Platt, T.; Rowland, F.; Wankar, P.; Bento, A.P.; Burdett, T.; Fabregat, A.; Forbes, S.; Gaulton, A.; Gonzalez, C.Y.; Hermjakob, H.; Hersey, A.; Jupe, S. Kafkas, Ş.; Keays, M.; Leroy, C.; Lopez, F.J.; Magarinos, M.P.; Malone, J.; McEntyre, J.; Munoz-Pomer Fuentes, A.; O’Donovan, C.; Papatheodorou, I.; Parkinson, H.; Palka, B.; Paschall, J.; Petryszak, R.; Pratanwanich, N.; Sarntivijal, S.; Saunders, G.; Sidiropoulos, K.; Smith, T.; Sondka, Z.; Stegle, O.; Tang, Y.A.; Turner, E.; Vaughan, B.; Vrousgou, O.; Watkins, X.; Martin, M.J.; Sanseau, P.; Vamathevan, J.; Birney, E.; Barrett, J.; Dunham, I. Open Targets: A platform for therapeutic target identification and validation. Nucleic Acids Res., 2017, 45(D1), D985-D994.
[http://dx.doi.org/10.1093/nar/gkw1055] [PMID: 27899665]
[11]
Matthews, H.; Hanison, J.; Nirmalan, N. “Omics”-informed drug and biomarker discovery: Opportunities, challenges and future perspectives. Proteomes, 2016, 4(3), 28-35.
[http://dx.doi.org/10.3390/proteomes4030028] [PMID: 28248238]
[12]
Amaratunga, D.; Gohlmann, H.; Peeters, P.J. Microarrays. Comprehensive Medicinal Chemistry II; Elsevier: Amsterdam, 2007, pp. 87-106.
[13]
Bemis, G.W.; Murcko, M.A. The properties of known drugs. 1. Molecular frameworks. J. Med. Chem., 1996, 39(15), 2887-2893.
[http://dx.doi.org/10.1021/jm9602928] [PMID: 8709122]
[14]
Zheng, C.J.; Han, L.Y.; Yap, C.W.; Ji, Z.L.; Cao, Z.W.; Chen, Y.Z. Therapeutic targets: Progress of their exploration and investigation of their characteristics. Pharmacol. Rev., 2006, 58(2), 259-279.
[http://dx.doi.org/10.1124/pr.58.2.4] [PMID: 16714488]
[15]
Russ, A.P.; Lampel, S. The druggable genome: An update. Drug Discov. Today, 2005, 10(23-24), 1607-1610.
[http://dx.doi.org/10.1016/S1359-6446(05)03666-4] [PMID: 16376820]
[16]
Hopkins, A.L.; Groom, C.R. The druggable genome. Nat. Rev. Drug Discov., 2002, 1(9), 727-730.
[http://dx.doi.org/10.1038/nrd892] [PMID: 12209152]
[17]
Bakheet, T.M.; Doig, A.J. Properties and identification of human protein drug targets. Bioinformatics, 2009, 25(4), 451-457.
[http://dx.doi.org/10.1093/bioinformatics/btp002] [PMID: 19164304]
[18]
Kim, B.; Jo, J.; Han, J.; Park, C.; Lee, H. In silico re-identification of properties of drug target proteins. BMC Bioinformatics, 2017, 18, 35-44.
[19]
Imming, P.; Sinning, C.; Meyer, A. Drugs, their targets and the nature and number of drug targets. Nat. Rev. Drug Discov., 2006, 5(10), 821-834.
[http://dx.doi.org/10.1038/nrd2132] [PMID: 17016423]
[20]
Diamantopoulos, M.A.; Tsiakanikas, P.; Scorilas, A. Non-coding RNAs: The riddle of the transcriptome and their perspectives in cancer. Ann. Transl. Med., 2018, 6(12), 241-248.
[http://dx.doi.org/10.21037/atm.2018.06.10] [PMID: 30069443]
[21]
Connelly, C.M.; Moon, M.H.; Schneekloth, J.S., Jr The emerging role of RNA as a therapeutic target for small molecules. Cell Chem. Biol., 2016, 23(9), 1077-1090.
[http://dx.doi.org/10.1016/j.chembiol.2016.05.021] [PMID: 27593111]
[22]
McKnight, K.L.; Heinz, B.A. RNA as a target for developing antivirals. Antivir. Chem. Chemother., 2003, 14(2), 61-73.
[http://dx.doi.org/10.1177/095632020301400201] [PMID: 12856917]
[23]
Dersch, P.; Khan, M.A.; Mühlen, S.; Görke, B. Roles of regulatory RNAs for antibiotic resistance in bacteria and their potential value as novel drug targets. Front. Microbiol., 2017, 8, 803-809.
[http://dx.doi.org/10.3389/fmicb.2017.00803] [PMID: 28529506]
[24]
Warner, K.D.; Hajdin, C.E.; Weeks, K.M. Principles for targeting RNA with drug-like small molecules. Nat. Rev. Drug Discov., 2018, 17(8), 547-558.
[http://dx.doi.org/10.1038/nrd.2018.93] [PMID: 29977051]
[25]
Sah, D.W.Y.; Aronin, N. Oligonucleotide therapeutic approaches for Huntington disease. J. Clin. Invest., 2011, 121(2), 500-507.
[http://dx.doi.org/10.1172/JCI45130] [PMID: 21285523]
[26]
Ozcan, G.; Ozpolat, B.; Coleman, R.L.; Sood, A.K.; Lopez-Berestein, G. Preclinical and clinical development of siRNA-based therapeutics. Adv. Drug Deliv. Rev., 2015, 87, 108-119.
[http://dx.doi.org/10.1016/j.addr.2015.01.007] [PMID: 25666164]
[27]
Boran, A.D.; Iyengar, R. Systems approaches to polypharmacology and drug discovery. Curr. Opin. Drug Discov. Devel., 2010, 13(3), 297-309.
[PMID: 20443163]
[28]
Sheng, Z.; Sun, Y.; Yin, Z.; Tang, K.; Cao, Z. Advances in computational approaches in identifying synergistic drug combinations. Brief. Bioinform., 2018, 19(6), 1172-1182.
[PMID: 28475767]
[29]
Vukovic, S.; Huggins, D.J. Quantitative metrics for drug-target ligandability. Drug Discov. Today, 2018, 23(6), 1258-1266.
[http://dx.doi.org/10.1016/j.drudis.2018.02.015] [PMID: 29522887]
[30]
Gashaw, I.; Ellinghaus, P.; Sommer, A.; Asadullah, K. What makes a good drug target? Drug Discov. Today, 2011, 16(23-24), 1037-1043.
[http://dx.doi.org/10.1016/j.drudis.2011.09.007] [PMID: 21945861]
[31]
Alexander-Dann, B.; Pruteanu, L.L.; Oerton, E.; Sharma, N.; Berindan-Neagoe, I.; Módos, D.; Bender, A. Developments in toxicogenomics: Understanding and predicting compound-induced toxicity from gene expression data. Mol. Omics, 2018, 14(4), 218-236.
[http://dx.doi.org/10.1039/C8MO00042E] [PMID: 29917034]
[32]
Cannon, D.C.; Yang, J.J.; Mathias, S.L.; Ursu, O.; Mani, S.; Waller, A.; Schürer, S.C.; Jensen, L.J.; Sklar, L.A.; Bologa, C.G.; Oprea, T.I. TIN-X: Target importance and novelty explorer. Bioinformatics, 2017, 33(16), 2601-2603.
[http://dx.doi.org/10.1093/bioinformatics/btx200] [PMID: 28398460]
[33]
Wei, C.H.; Kao, H.Y.; Lu, Z. PubTator: A web-based text mining tool for assisting biocuration. Nucleic Acids Res., 2013, 41(W1), W518-W522.
[http://dx.doi.org/10.1093/nar/gkt441] [PMID: 23703206]
[34]
Capuzzi, S.J.; Thornton, T.E.; Liu, K.; Baker, N.; Lam, W.I.; O’Banion, C.P.; Muratov, E.N.; Pozefsky, D.; Tropsha, A. Chemotext: A publicly available web server for mining drug-target-disease relationships in PubMed. J. Chem. Inf. Model., 2018, 58(2), 212-218.
[http://dx.doi.org/10.1021/acs.jcim.7b00589] [PMID: 29300482]
[35]
Percha, B.; Altman, R.B. A global network of biomedical relationships derived from text. Bioinformatics, 2018, 34(15), 2614-2624.
[http://dx.doi.org/10.1093/bioinformatics/bty114] [PMID: 29490008]
[36]
Zhu, S.; Bing, J.; Min, X.; Lin, C.; Zeng, X. Prediction of drug-gene interaction by using metapath2vec. Front. Genet., 2018, 9, 248-254.
[http://dx.doi.org/10.3389/fgene.2018.00248] [PMID: 30108606]
[37]
Stoeger, T.; Gerlach, M.; Morimoto, R.I.; Nunes Amaral, L.A. Large-scale investigation of the reasons why potentially important genes are ignored. PLoS Biol., 2018, 16(9), e2006643.
[http://dx.doi.org/10.1371/journal.pbio.2006643] [PMID: 30226837]
[38]
Bolognesi, M.L.; Cavalli, A. Multitarget drug discovery and polypharmacology. ChemMedChem, 2016, 11(12), 1190-1192.
[http://dx.doi.org/10.1002/cmdc.201600161] [PMID: 27061625]
[39]
Talevi, A. Multi-target pharmacology: Possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective. Front. Pharmacol., 2015, 6, 205-209.
[http://dx.doi.org/10.3389/fphar.2015.00205] [PMID: 26441661]
[40]
Vakil, V.; Trappe, W. Drug combinations: Mathematical modeling and networking methods. Pharmaceutics, 2019, 11(5), 208-213.
[http://dx.doi.org/10.3390/pharmaceutics11050208] [PMID: 31052580]
[41]
Al-Lazikani, B.; Banerji, U.; Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol., 2012, 30(7), 679-692.
[http://dx.doi.org/10.1038/nbt.2284] [PMID: 22781697]
[42]
Santos, R.; Ursu, O.; Gaulton, A.; Bento, A.P.; Donadi, R.S.; Bologa, C.G.; Karlsson, A.; Al-Lazikani, B.; Hersey, A.; Oprea, T.I.; Overington, J.P. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov., 2017, 16(1), 19-34.
[http://dx.doi.org/10.1038/nrd.2016.230] [PMID: 27910877]
[43]
Brennan, R.J. Target safety assessment: Strategies and resources. Methods Mol. Biol., 2017, 1641, 213-228.
[http://dx.doi.org/10.1007/978-1-4939-7172-5_12] [PMID: 28748467]
[44]
Chen, X.; Ji, Z.L.; Chen, Y.Z. TTD: Therapeutic target database. Nucleic Acids Res., 2002, 30(1), 412-415.
[http://dx.doi.org/10.1093/nar/30.1.412] [PMID: 11752352]
[45]
Wishart, D.S.; Knox, C.; Guo, A.C.; Shrivastava, S.; Hassanali, M.; Stothard, P.; Chang, Z.; Woolsey, J. DrugBank: A comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res., 2006, 34(90001), D668-D672.
[http://dx.doi.org/10.1093/nar/gkj067] [PMID: 16381955]
[46]
Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[47]
Foucquier, J.; Guedj, M. Analysis of drug combinations: Current methodological landscape. Pharmacol. Res. Perspect., 2015, 3(3), e00149.
[http://dx.doi.org/10.1002/prp2.149] [PMID: 26171228]
[48]
McKusick, V.A. Genomics: Structural and functional studies of genomes. Genomics, 1997, 45(2), 244-249.
[http://dx.doi.org/10.1006/geno.1997.5020] [PMID: 9463089]
[49]
National Human Genome Research Institute. FAQ about genetic and genomic science; Genome. Gov, 2010.
[50]
Ward, S.J. Impact of genomics in drug discovery. Biotechniques, 2001, 31(3), 626-634.
[http://dx.doi.org/10.2144/01313dd01] [PMID: 11570506]
[51]
Emilien, G.; Ponchon, M.; Caldas, C.; Isacson, O.; Maloteaux, J.M. Impact of genomics on drug discovery and clinical medicine. QJM, 2000, 93(7), 391-423.
[http://dx.doi.org/10.1093/qjmed/93.7.391] [PMID: 10874050]
[52]
Hewick, R.M.; Lu, Z.; Wang, J.H. Proteomics in drug discovery. Adv. Protein Chem., 2003, 65, 309-342.
[http://dx.doi.org/10.1016/S0065-3233(03)01024-6] [PMID: 12964374]
[53]
Wang, J.H.; Hewick, R.M. Proteomics in drug discovery. Drug Discov. Today, 1999, 4(3), 129-133.
[http://dx.doi.org/10.1016/S1359-6446(99)01306-9] [PMID: 10322265]
[54]
Ahn, N.G.; Wang, A.H.J. Proteomics and genomics: Perspectives on drug and target discovery. Curr. Opin. Chem. Biol., 2008, 12(1), 1-3.
[http://dx.doi.org/10.1016/j.cbpa.2008.02.016] [PMID: 18302945]
[55]
Veenstra, T.D. Proteomic approaches in drug discovery. Drug Discov. Today. Technol., 2006, 3(4), 433-440.
[http://dx.doi.org/10.1016/j.ddtec.2006.10.001]
[56]
Schenone, M. Dančík, V.; Wagner, B.K.; Clemons, P.A. Target identification and mechanism of action in chemical biology and drug discovery. Nat. Chem. Biol., 2013, 9(4), 232-240.
[http://dx.doi.org/10.1038/nchembio.1199] [PMID: 23508189]
[57]
Zhang, H.M.; Nan, Z.R.; Hui, G.Q.; Liu, X.H.; Sun, Y. Application of genomics and proteomics in drug target discovery. Genet. Mol. Res., 2014, 13(1), 198-204.
[http://dx.doi.org/10.4238/2014.January.10.11] [PMID: 24446303]
[58]
Blazer, L.L.; Neubig, R.R. Small molecule protein-protein interaction inhibitors as CNS therapeutic agents: Current progress and future hurdles. Neuropsychopharmacology, 2009, 34(1), 126-141.
[http://dx.doi.org/10.1038/npp.2008.151] [PMID: 18800065]
[59]
Rosell, M.; Fernández-Recio, J. Hot-spot analysis for drug discovery targeting protein-protein interactions. Expert Opin. Drug Discov., 2018, 13(4), 327-338.
[http://dx.doi.org/10.1080/17460441.2018.1430763] [PMID: 29376444]
[60]
Nevola, L.; Giralt, E. Modulating protein-protein interactions: The potential of peptides. Chem. Commun. (Camb.), 2015, 51(16), 3302-3315.
[http://dx.doi.org/10.1039/C4CC08565E] [PMID: 25578807]
[61]
Scott, D.E.; Bayly, A.R.; Abell, C.; Skidmore, J. Small molecules, big targets: Drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Discov., 2016, 15(8), 533-550.
[http://dx.doi.org/10.1038/nrd.2016.29] [PMID: 27050677]
[62]
Wang, Y.; Chiu, J.F.; He, Q.Y. Genomics and proteomics in drug design and discovery. In: Pharmacology: Principles and Practice; Hacker, M.; Messer, W.S.; Bachmann, K.A., Eds.; Academic Press: USA, 2009; pp. 561-573.
[63]
Rabilloud, T.; Lelong, C. Two-dimensional gel electrophoresis in proteomics: A tutorial. J. Proteomics, 2011, 74(10), 1829-1841.
[http://dx.doi.org/10.1016/j.jprot.2011.05.040] [PMID: 21669304]
[64]
Penque, D. Two-dimensional gel electrophoresis and mass spectrometry for biomarker discovery. Proteomics Clin. Appl., 2009, 3(2), 155-172.
[http://dx.doi.org/10.1002/prca.200800025] [PMID: 26238616]
[65]
Bonk, T.; Humeny, A. MALDI-TOF-MS analysis of protein and DNA. Neuroscientist, 2001, 7(1), 6-12.
[http://dx.doi.org/10.1177/107385840100700104] [PMID: 11486345]
[66]
Roepstorff, P. MALDI-TOF mass spectrometry in protein chemistry. Proteomics in Funct. Genomics, 2000, 3, 81-97.
[67]
Schirle, M.; Bantscheff, M.; Kuster, B. Mass spectrometry-based proteomics in preclinical drug discovery. Chem. Biol., 2012, 19(1), 72-84.
[http://dx.doi.org/10.1016/j.chembiol.2012.01.002] [PMID: 22284356]
[68]
Karpievitch, Y.V.; Polpitiya, A.D.; Anderson, G.A.; Smith, R.D.; Dabney, A.R. Liquid chromatography mass spectrometry-based proteomics: Biological and technological aspects. Ann. Appl. Stat., 2010, 4(4), 1797-1823.
[http://dx.doi.org/10.1214/10-AOAS341] [PMID: 21593992]
[69]
Chandramouli, K.; Qian, P.Y. Proteomics: challenges, techniques and possibilities to overcome biological sample complexity. Hum. Genomics Proteomics, 2009, 2009, 1-10.
[70]
Cutler, P. Protein arrays: The current state-of-the-art. Proteomics, 2003, 3(1), 3-18.
[http://dx.doi.org/10.1002/pmic.200390007] [PMID: 12548629]
[71]
Schweitzer, B.; Kingsmore, S.F. Measuring proteins on microarrays. Curr. Opin. Biotechnol., 2002, 13(1), 14-19.
[http://dx.doi.org/10.1016/S0958-1669(02)00278-1] [PMID: 11849952]
[72]
Hall, D.A.; Zhu, H.; Zhu, X.; Royce, T.; Gerstein, M.; Snyder, M. Regulation of gene expression by a metabolic enzyme. Science, 2004, 306(5695), 482-484.
[http://dx.doi.org/10.1126/science.1096773] [PMID: 15486299]
[73]
Zhu, H.; Bilgin, M.; Bangham, R.; Hall, D.; Casamayor, A.; Bertone, P.; Lan, N.; Jansen, R.; Bidlingmaier, S.; Houfek, T.; Mitchell, T.; Miller, P.; Dean, R.A.; Gerstein, M.; Snyder, M. Global analysis of protein activities using proteome chips. Science, 2001, 293(5537), 2101-2105.
[http://dx.doi.org/10.1126/science.1062191] [PMID: 11474067]

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