Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/20156

Type
Article
Copyright
Restricted access
Embargo date
2030-01-01
Sustainable Development Goals
03 Saúde e Bem-Estar
Collections
Share

Statistics
Metadata
Show full item record

DISCOVERY OF NEW ANTI-SCHISTOSOMAL HITS BY INTEGRATION OF QSAR-BASED VIRTUAL SCREENING AND HIGH CONTENT SCREENING
Neves, Bruno J. et al. | Date Issued: 2016
Author
Neves, Bruno J.
Dantas, Rafael F.
Senger, Mario R.
Valente, Walter C. G.
Almeida, Ana C. M. de
Rezende Neto, João M.
Lima, Elid F. C.
Paveley, Ross
Furnham, Nicholas
Muratov, Eugene
Kamentsky, Lee
Carpenter, Anne E.
Braga, Rodolfo C.
Silva Junior, Floriano P.
Andrade, Carolina H.
Affilliation
Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ, Brasil.
Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ. Brasil.
London School of Hygiene and Tropical Medicine. Department of Infection and Immunity. London, United Kingdom.
London School of Hygiene and Tropical Medicine. Department of Infection and Immunity. London, United Kingdom.
University of North Carolina. Eshelman School of Pharmacy. Laboratory for Molecular Modeling. Chapel Hill, NC, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard. Imaging Platform.Cambridge, Massachusetts, USA..
Broad Institute of Massachussetts Institute of Technology and Harvard. Imaging Platform. Cambridge, Massachussetts, USA.
Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.
Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.
Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.
Abstract
Schistosomiasis is a debilitating neglected tropical disease, caused by flatworms of Schistosoma genus. The treatment relies on a single drug, praziquantel (PZQ), making the discovery of new compounds extremely urgent. In this work, we integrated QSAR-based virtual screening (VS) of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) inhibitors and high content screening (HCS) aiming to discover new antischistosomal agents. Initially, binary QSAR models for inhibition of SmTGR were developed and validated using the Organization for Economic Co-operation and Development (OECD) guidance. Using these models, we prioritized 29 compounds for further testing in two HCS platforms based on image analysis of assay plates. Among them, 2-[2-(3-methyl-4-nitro-5-isoxazolyl)vinyl]pyridine and 2-(benzylsulfonyl)-1,3-benzothiazole, two compounds representing new chemical scaffolds have activity against schistosomula and adult worms at low micromolar concentrations and therefore represent promising antischistosomal hits for further hit-to-lead optimization.
Keywords in Portuguese
Medicina molecular
Esquistossomose
Doenças Negligenciadas
 
Keywords
Schistosoma mansoni
Schistosomiasis
Neglected Diseases
Molecular Medicine
Neglected Diseases
 
Publisher
American Chemical Society
Citation
NEVES, Bruno J. et al. Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening. Journal of Medicinal Chemistry, v.59, n.15, p.7075-7088, Aug. 2016.
ISSN
0022-2623