title: Cheminformatics models for inhibitors of Schistosoma mansoni thioredoxin glutathione reductase.
abstract: Schistosomiasis is a neglected tropical disease caused by a parasite Schistosoma mansoni and affects over 200 million annually. There is an urgent need to discover novel therapeutic options to control the disease with the recent emergence of drug resistance. The multifunctional protein, thioredoxin glutathione reductase (TGR), an essential enzyme for the survival of the pathogen in the redox environment has been actively explored as a potential drug target. The recent availability of small-molecule screening datasets against this target provides a unique opportunity to learn molecular properties and apply computational models for discovery of activities in large molecular libraries. Such a prioritisation approach could have the potential to reduce the cost of failures in lead discovery. A supervised learning approach was employed to develop a cost sensitive classification model to evaluate the biological activity of the molecules. Random forest was identified to be the best classifier among all the classifiers with an accuracy of around 80 percent. Independent analysis using a maximally occurring substructure analysis revealed 10 highly enriched scaffolds in the actives dataset and their docking against was also performed. We show that a combined approach of machine learning and other cheminformatics approaches such as substructure comparison and molecular docking is efficient to prioritise molecules from large molecular datasets.
authors: GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
authors: Sonam
authors: S
authors: Gaba
authors: CSIR Open Source Drug Discovery Unit, Anusandhan Bhawan, 2 Rafi Marg, Delhi 110001, India.
authors: Salma
authors: S
authors: Jamal
authors: CSIR Open Source Drug Discovery Unit, Anusandhan Bhawan, 2 Rafi Marg, Delhi 110001, India.
authors: Open Source Drug Discovery Consortium
authors: GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India.
authors: Vinod
authors: 0000-0001-7644-7181
authors: V
authors: Scaria
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D012550:Schistosoma mansoni / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D009097:Multienzyme Complexes; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase
references: Trends Microbiol. 2002 Oct;10(10):435-40
references: 12377547
references: Assay Drug Dev Technol. 2008 Aug;6(4):551-5
references: 18665782
references: Prog Med Chem. 2000;37:83-133
references: 10845248
references: J Biol Chem. 2010 Oct 15;285(42):32557-67
references: 20659890
references: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W623-33
references: 19498078
references: Acta Trop. 2002 May;82(2):139-46
references: 12020886
references: J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
references: 15667143
references: J Biol Chem. 2009 Oct 16;284(42):28977-85
references: 19710012
references: Antimicrob Agents Chemother. 2003 May;47(5):1487-95
references: 12709312
references: BMC Bioinformatics. 2013;14:55
references: 23419172
references: J Comput Chem. 2004 Oct;25(13):1605-12
references: 15264254
references: PLoS Negl Trop Dis. 2008;2(1):e127
references: 18235848
references: BMC Bioinformatics. 2010;11:523
references: 20961420
references: PLoS Med. 2007 Jun;4(6):e206
references: 17579510
references: Comb Chem High Throughput Screen. 2009 May;12(4):332-43
references: 19442063
references: BMC Pharmacol. 2012;12:1
references: 22463123
references: Curr Opin Infect Dis. 2008 Dec;21(6):659-67
references: 18978535
references: Proteins. 2008 Aug 15;72(3):936-45
references: 18300227
references: BMC Res Notes. 2011 Nov 18;4:504
references: 22099929
references: Nat Rev Drug Discov. 2006 Nov;5(11):941-55
references: 17080030
references: J Chem Inf Model. 2005 Mar-Apr;45(2):515-22
references: 15807517
references: J Cheminform. 2011 Oct 07;3:33
references: 21982300
references: Int J Med Microbiol. 2000 May;290(2):191-201
references: 11045924
references: Am J Trop Med Hyg. 1994 Jul;51(1):83-8
references: 8059919
references: J Cheminform. 2012 Aug 13;4(1):16
references: 22889302
references: Lancet Infect Dis. 2006 Jul;6(7):411-25
references: 16790382
references: World Health Organ Tech Rep Ser. 2002;912:i-vi, 1-57, back cover
references: 12592987