QSAR-Driven Discovery of Novel Chemical Scaffolds Active...

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J. Chem. Inf. Model.All Publications/WebsiteOR SEARCH CITATIONS Recently ViewedYou have not visited any articles yet, Please visit some articles to see contents here. RETURN TO ISSUEPREVArticleNEXTQSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoniCleber C. Melo-Filho†,Rafael F. Dantas‡,Rodolpho C. Braga†,Bruno J. Neves†,Mario R. Senger‡,Walter C. G. Valente‡,João M. Rezende-Neto‡,Willian T. Chaves‡,Eugene N. Muratov§∥,Ross A. Paveley⊥,Nicholas Furnham⊥,Lee Kamentsky#,Anne E. Carpenter#,Floriano P. Silva-Junior*‡,andCarolina H. Andrade*†View Author Information† LabMol−Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias, Rua 240, Qd.87, Goiania, GO 74605-510, Brazil‡ Laboratory of Experimental and Computational Biochemistry of Drugs, Oswaldo Cruz Institute, Av. Brasil, 4365, Rio de Janeiro, RJ 21040-900, Brazil§ Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States∥ Department of Chemical Technology, Odessa National Polytechnic University, 1. Shevchenko Ave., Odessa, 65000, Ukraine⊥ Department of Pathogen Molecular Biology Department of Infection and Immunity, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom# Imaging Platform, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, United States*Tel.: + 55 21 3865 8248. Fax: +55 21 2590 3495. E-mail: [email protected]*Tel.: + 55 62 3209 6451. Fax: +55 62 3209 6037. E-mail: [email protected]Cite this: J. Chem. Inf. Model. 2016, 56, 7, 1357–1372Publication Date (Web):June 2, 2016Publication History Received3 February 2016Published online16 June 2016Published inissue 25 July 2016https://doi.org/10.1021/acs.jcim.6b00055Copyright © 2016 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views806Altmetric-Citations33LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.Get e-AlertsAbstractSchistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure–activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents.Supporting InformationARTICLE SECTIONSJump ToThe Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jcim.6b00055.Statistical characteristics for the three best HQSAR models obtained using different combinations of fragment distinction, fragment size, and hologram length (Table S1). Experimental and predicted potencies (pIC50) for the test set compounds using the best HQSAR, CoMFA, and CoMSIA models (Table S2). Best CoMFA models obtained using different charge-assigning and alignment methods (Table S3). Best CoMSIA models generated using different charge-assigning and alignment methods (Table S4). Chemical structures and predicted biological activities (pIC50 and IC50) using the best consensus QSAR model for the lead compound (33) and the identified hits (Table S5). Experimental versus predicted biological activity of the best HQSAR (A); CoMFA (B); and CoMSIA (C) models (Figure S1) (PDF)ci6b00055_si_001.pdf (476.25 kb) Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html. Cited ByThis article is cited by 33 publications.ViniciusM. Alves, Alexander Golbraikh, Stephen J. Capuzzi, Kammy Liu, Wai In Lam, Daniel Robert Korn, Diane Pozefsky, Carolina Horta Andrade, Eugene N. Muratov, Alexander Tropsha. Multi-Descriptor Read Across (MuDRA): A Simple and Transparent Approach for Developing Accurate Quantitative Structure–Activity Relationship Models. 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