QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni

Detalhes bibliográficos
Autor(a) principal: Melo Filho, Cleber C.
Data de Publicação: 2016
Outros Autores: Dantas, Rafael F., Braga, Rodolpho C., Neves, Bruno J., Senger, Mario R., Valente, Walter C. G., Rezende.Neto, João M., Chaves, Willian T., Muratov, Eugene N., Paveley, Ross A., Furnham, Nicholas, Kamentsky, Lee, Carpenter, Anne E., Silva.Junior, Floriano P., Andrade, Carolina H.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/19408
Resumo: 2016-01-01
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spelling Melo Filho, Cleber C.Dantas, Rafael F.Braga, Rodolpho C.Neves, Bruno J.Senger, Mario R.Valente, Walter C. G.Rezende.Neto, João M.Chaves, Willian T.Muratov, Eugene N.Paveley, Ross A.Furnham, NicholasKamentsky, LeeCarpenter, Anne E.Silva.Junior, Floriano P.Andrade, Carolina H.2017-06-19T17:45:23Z2017-06-19T17:45:23Z2016MELO FILHO, Cleber C. et al. QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni. J. Chem. Inf. Model., v.56, p.1357−1372, June 2016.1549-9596https://www.arca.fiocruz.br/handle/icict/1940810.1021/acs.jcim.6b000551549-960XengAmerican Chemical SocietySchistosoma mansoniRelação Quantitativa Estrutura-AtividadeNovos suportes químicosSchistosoma mansoniQSARNovel Chemical ScaffoldsQSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoniinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article2016-01-01Universidade Federal de Goiás. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular (LabMol). Goiânia, GO, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ. Brasil.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular (LabMol). Goiânia, GO, Brasil.Universidade Federal de Goiás. Faculdade de Farmácia.Laboratório de Planejamento de Fármacos e Modelagem Molecular (LabMol). 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.University of North Carolina. Eshelman School of Pharmacy. Division of Chemical Biology and Medicinal Chemistry. Laboratory for Molecular Modeling. Chapel Hill, North Carolina, USA / Odessa National Polytechnic University. Department of Chemical Technology. Odessa, Ukraine.London School of Hygiene and Tropical Medicine. Department of Pathogen Molecular Biology & Department of Infection and Immunity. London, United Kingdom.London School of Hygiene and Tropical Medicine. Department of Pathogen Molecular Biology & Department of Infection and Immunity. London, United Kingdom.Broad Institute of Massachusetts Institute of Technology and Harvard. Imaging Platform.Cambridge, Massachusetts, USA.Broad Institute of Massachusetts Institute of Technology and Harvard. Imaging Platform.Cambridge, Massachusetts, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ. Brasil.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular (LabMol). Goiânia, GO, Brasil.Schistosomiasis 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.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/19408/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALmario2_senger_etal_IOC_2016.pdfmario2_senger_etal_IOC_2016.pdfapplication/pdf8232715https://www.arca.fiocruz.br/bitstream/icict/19408/2/mario2_senger_etal_IOC_2016.pdf18b8f8061c2200055931f3faf0acbbaeMD52TEXTmario2_senger_etal_IOC_2016.pdf.txtmario2_senger_etal_IOC_2016.pdf.txtExtracted texttext/plain68812https://www.arca.fiocruz.br/bitstream/icict/19408/3/mario2_senger_etal_IOC_2016.pdf.txtc46332cf23a0cbf4090a0a4b605da91dMD53icict/194082021-03-24 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dc.title.pt_BR.fl_str_mv QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
title QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
spellingShingle QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
Melo Filho, Cleber C.
Schistosoma mansoni
Relação Quantitativa Estrutura-Atividade
Novos suportes químicos
Schistosoma mansoni
QSAR
Novel Chemical Scaffolds
title_short QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
title_full QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
title_fullStr QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
title_full_unstemmed QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
title_sort QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni
author Melo Filho, Cleber C.
author_facet Melo Filho, Cleber C.
Dantas, Rafael F.
Braga, Rodolpho C.
Neves, Bruno J.
Senger, Mario R.
Valente, Walter C. G.
Rezende.Neto, João M.
Chaves, Willian T.
Muratov, Eugene N.
Paveley, Ross A.
Furnham, Nicholas
Kamentsky, Lee
Carpenter, Anne E.
Silva.Junior, Floriano P.
Andrade, Carolina H.
author_role author
author2 Dantas, Rafael F.
Braga, Rodolpho C.
Neves, Bruno J.
Senger, Mario R.
Valente, Walter C. G.
Rezende.Neto, João M.
Chaves, Willian T.
Muratov, Eugene N.
Paveley, Ross A.
Furnham, Nicholas
Kamentsky, Lee
Carpenter, Anne E.
Silva.Junior, Floriano P.
Andrade, Carolina H.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Melo Filho, Cleber C.
Dantas, Rafael F.
Braga, Rodolpho C.
Neves, Bruno J.
Senger, Mario R.
Valente, Walter C. G.
Rezende.Neto, João M.
Chaves, Willian T.
Muratov, Eugene N.
Paveley, Ross A.
Furnham, Nicholas
Kamentsky, Lee
Carpenter, Anne E.
Silva.Junior, Floriano P.
Andrade, Carolina H.
dc.subject.other.pt_BR.fl_str_mv Schistosoma mansoni
Relação Quantitativa Estrutura-Atividade
Novos suportes químicos
topic Schistosoma mansoni
Relação Quantitativa Estrutura-Atividade
Novos suportes químicos
Schistosoma mansoni
QSAR
Novel Chemical Scaffolds
dc.subject.en.pt_BR.fl_str_mv Schistosoma mansoni
QSAR
Novel Chemical Scaffolds
description 2016-01-01
publishDate 2016
dc.date.issued.fl_str_mv 2016
dc.date.accessioned.fl_str_mv 2017-06-19T17:45:23Z
dc.date.available.fl_str_mv 2017-06-19T17:45:23Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv MELO FILHO, Cleber C. et al. QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni. J. Chem. Inf. Model., v.56, p.1357−1372, June 2016.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/19408
dc.identifier.issn.pt_BR.fl_str_mv 1549-9596
dc.identifier.doi.none.fl_str_mv 10.1021/acs.jcim.6b00055
dc.identifier.eissn.none.fl_str_mv 1549-960X
identifier_str_mv MELO FILHO, Cleber C. et al. QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni. J. Chem. Inf. Model., v.56, p.1357−1372, June 2016.
1549-9596
10.1021/acs.jcim.6b00055
1549-960X
url https://www.arca.fiocruz.br/handle/icict/19408
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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https://www.arca.fiocruz.br/bitstream/icict/19408/2/mario2_senger_etal_IOC_2016.pdf
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