Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

Detalhes bibliográficos
Autor(a) principal: Nunes,Renata Rachide
Data de Publicação: 2016
Outros Autores: Costa,Marina dos Santos, Santos,Bianca dos Reis, Fonseca,Amanda Luisa da, Ferreira,Lorena Sales, Chagas,Rafael Cesar Russo, Silva,Alisson Marques da, Varotti,Fernando de Pilla, Taranto,Alex Gutterres
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Memórias do Instituto Oswaldo Cruz
Texto Completo: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762016001200721
Resumo: The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.
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spelling Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targetsPlasmodium falciparumplasmepsin-IIplasmepsin-IVfalcipain-IIPfATP6virtual screeningThe main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.Instituto Oswaldo Cruz, Ministério da Saúde2016-12-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762016001200721Memórias do Instituto Oswaldo Cruz v.111 n.12 2016reponame:Memórias do Instituto Oswaldo Cruzinstname:Fundação Oswaldo Cruzinstacron:FIOCRUZ10.1590/0074-02760160207info:eu-repo/semantics/openAccessNunes,Renata RachideCosta,Marina dos SantosSantos,Bianca dos ReisFonseca,Amanda Luisa daFerreira,Lorena SalesChagas,Rafael Cesar RussoSilva,Alisson Marques daVarotti,Fernando de PillaTaranto,Alex Gutterreseng2020-04-25T17:52:30Zhttp://www.scielo.br/oai/scielo-oai.php0074-02761678-8060opendoar:null2020-04-26 02:21:30.496Memórias do Instituto Oswaldo Cruz - Fundação Oswaldo Cruztrue
dc.title.none.fl_str_mv Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
title Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
spellingShingle Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
Nunes,Renata Rachide
Plasmodium falciparum
plasmepsin-II
plasmepsin-IV
falcipain-II
PfATP6
virtual screening
title_short Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
title_full Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
title_fullStr Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
title_full_unstemmed Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
title_sort Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
author Nunes,Renata Rachide
author_facet Nunes,Renata Rachide
Costa,Marina dos Santos
Santos,Bianca dos Reis
Fonseca,Amanda Luisa da
Ferreira,Lorena Sales
Chagas,Rafael Cesar Russo
Silva,Alisson Marques da
Varotti,Fernando de Pilla
Taranto,Alex Gutterres
author_role author
author2 Costa,Marina dos Santos
Santos,Bianca dos Reis
Fonseca,Amanda Luisa da
Ferreira,Lorena Sales
Chagas,Rafael Cesar Russo
Silva,Alisson Marques da
Varotti,Fernando de Pilla
Taranto,Alex Gutterres
author2_role author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Nunes,Renata Rachide
Costa,Marina dos Santos
Santos,Bianca dos Reis
Fonseca,Amanda Luisa da
Ferreira,Lorena Sales
Chagas,Rafael Cesar Russo
Silva,Alisson Marques da
Varotti,Fernando de Pilla
Taranto,Alex Gutterres
dc.subject.por.fl_str_mv Plasmodium falciparum
plasmepsin-II
plasmepsin-IV
falcipain-II
PfATP6
virtual screening
topic Plasmodium falciparum
plasmepsin-II
plasmepsin-IV
falcipain-II
PfATP6
virtual screening
dc.description.none.fl_txt_mv The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.
description The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.
publishDate 2016
dc.date.none.fl_str_mv 2016-12-01
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762016001200721
url http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762016001200721
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 10.1590/0074-02760160207
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv text/html
dc.publisher.none.fl_str_mv Instituto Oswaldo Cruz, Ministério da Saúde
publisher.none.fl_str_mv Instituto Oswaldo Cruz, Ministério da Saúde
dc.source.none.fl_str_mv Memórias do Instituto Oswaldo Cruz v.111 n.12 2016
reponame:Memórias do Instituto Oswaldo Cruz
instname:Fundação Oswaldo Cruz
instacron:FIOCRUZ
reponame_str Memórias do Instituto Oswaldo Cruz
collection Memórias do Instituto Oswaldo Cruz
instname_str Fundação Oswaldo Cruz
instacron_str FIOCRUZ
institution FIOCRUZ
repository.name.fl_str_mv Memórias do Instituto Oswaldo Cruz - Fundação Oswaldo Cruz
repository.mail.fl_str_mv
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