Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies

Detalhes bibliográficos
Autor(a) principal: Coutinho, Julia Penna
Data de Publicação: 2011
Outros Autores: Cortopassi, Wilian Augusto, Oliveira, Aline Alves, França, Tanos Celmar Costa, Krettli, Antoniana Ursine
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/8642
Resumo: MCT/CNPq/CT-Saúde/MS/SCTIE/DECIT, FIOCRUZ-PAPES, FAPEMIG and FAPERJ, and by CNPq
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spelling Coutinho, Julia PennaCortopassi, Wilian AugustoOliveira, Aline AlvesFrança, Tanos Celmar CostaKrettli, Antoniana Ursine2014-10-21T16:37:55Z2014-10-21T16:37:55Z2011COUTINHO, Julia Penna et al. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies. PLoS One 6(7): e21237, 20111932-6203https://www.arca.fiocruz.br/handle/icict/864210.1371/journal.pone.0021237MCT/CNPq/CT-Saúde/MS/SCTIE/DECIT, FIOCRUZ-PAPES, FAPEMIG and FAPERJ, and by CNPqUniversidade Federal de Minas Gerais. Faculdade de Medicina. Belo Horizonte, MG, Brazil/Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Laboratório de Malária. Belo Horizonte, MG, BrazilMilitary Institute of Engineering Defense. Laboratory of Molecular Modeling Applied to the Chemical and Biological. Rio de Janeiro, RJ, BrazilMilitary Institute of Engineering Defense. Laboratory of Molecular Modeling Applied to the Chemical and Biological. Rio de Janeiro, RJ, BrazilMilitary Institute of Engineering Defense. Laboratory of Molecular Modeling Applied to the Chemical and Biological. Rio de Janeiro, RJ, BrazilUniversidade Federal de Minas Gerais. Faculdade de Medicina. Belo Horizonte, MG, Brazil/Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazil,The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH) has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH) all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH) and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole) were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2). The IC(50) values for each drug in both tests were similar, were lowest for posaconazole (<5 µM) and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use.engPublic Library of Science oneAntimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studiesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleAntimalarials/pharmacologyAntimalarials/therapeutic useHydroxymethylglutaryl-CoA Reductase Inhibitors/chemistryItraconazole/pharmacologyinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-81914https://www.arca.fiocruz.br/bitstream/icict/8642/1/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD51ORIGINALAntimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.pdfAntimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.pdfapplication/pdf328630https://www.arca.fiocruz.br/bitstream/icict/8642/2/Antimalarial%20activity%20of%20potential%20inhibitors%20of%20Plasmodium%20falciparum%20lactate%20dehydrogenase%20enzyme%20selected%20by%20docking%20studies.pdf2172de1080eb94b618102c200228768cMD52TEXTAntimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.pdf.txtAntimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.pdf.txtExtracted texttext/plain40972https://www.arca.fiocruz.br/bitstream/icict/8642/3/Antimalarial%20activity%20of%20potential%20inhibitors%20of%20Plasmodium%20falciparum%20lactate%20dehydrogenase%20enzyme%20selected%20by%20docking%20studies.pdf.txt675e80d0d533b74157b8067622154f3cMD53icict/86422019-06-19 10:12:16.733oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352019-06-19T13:12:16Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false
dc.title.pt_BR.fl_str_mv Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
title Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
spellingShingle Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
Coutinho, Julia Penna
Antimalarials/pharmacology
Antimalarials/therapeutic use
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry
Itraconazole/pharmacology
title_short Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
title_full Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
title_fullStr Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
title_full_unstemmed Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
title_sort Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies
author Coutinho, Julia Penna
author_facet Coutinho, Julia Penna
Cortopassi, Wilian Augusto
Oliveira, Aline Alves
França, Tanos Celmar Costa
Krettli, Antoniana Ursine
author_role author
author2 Cortopassi, Wilian Augusto
Oliveira, Aline Alves
França, Tanos Celmar Costa
Krettli, Antoniana Ursine
author2_role author
author
author
author
dc.contributor.author.fl_str_mv Coutinho, Julia Penna
Cortopassi, Wilian Augusto
Oliveira, Aline Alves
França, Tanos Celmar Costa
Krettli, Antoniana Ursine
dc.subject.en.pt_BR.fl_str_mv Antimalarials/pharmacology
Antimalarials/therapeutic use
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry
Itraconazole/pharmacology
topic Antimalarials/pharmacology
Antimalarials/therapeutic use
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry
Itraconazole/pharmacology
description MCT/CNPq/CT-Saúde/MS/SCTIE/DECIT, FIOCRUZ-PAPES, FAPEMIG and FAPERJ, and by CNPq
publishDate 2011
dc.date.issued.fl_str_mv 2011
dc.date.accessioned.fl_str_mv 2014-10-21T16:37:55Z
dc.date.available.fl_str_mv 2014-10-21T16:37:55Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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status_str publishedVersion
dc.identifier.citation.fl_str_mv COUTINHO, Julia Penna et al. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies. PLoS One 6(7): e21237, 2011
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/8642
dc.identifier.issn.none.fl_str_mv 1932-6203
dc.identifier.doi.none.fl_str_mv 10.1371/journal.pone.0021237
identifier_str_mv COUTINHO, Julia Penna et al. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies. PLoS One 6(7): e21237, 2011
1932-6203
10.1371/journal.pone.0021237
url https://www.arca.fiocruz.br/handle/icict/8642
dc.language.iso.fl_str_mv eng
language eng
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dc.publisher.none.fl_str_mv Public Library of Science one
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dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
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