Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , |
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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Memórias do Instituto Oswaldo Cruz |
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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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1669937722577387520 |