Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
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 virtu...
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| Format: | Article |
| Language: | English |
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Fundação Oswaldo Cruz (FIOCRUZ)
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| Series: | Memorias do Instituto Oswaldo Cruz |
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| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762016005023101&lng=en&tlng=en |
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| author | Renata Rachide Nunes Marina dos Santos Costa Bianca dos Reis Santos Amanda Luisa da Fonseca Lorena Sales Ferreira Rafael Cesar Russo Chagas Alisson Marques da Silva Fernando de Pilla Varotti Alex Gutterres Taranto |
| author_facet | Renata Rachide Nunes Marina dos Santos Costa Bianca dos Reis Santos Amanda Luisa da Fonseca Lorena Sales Ferreira Rafael Cesar Russo Chagas Alisson Marques da Silva Fernando de Pilla Varotti Alex Gutterres Taranto |
| author_sort | Renata Rachide Nunes |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T08:48:33Z |
| format | Article |
| id | doaj.art-2a68d8814cae46f1a21abc049b64dfa3 |
| institution | Directory Open Access Journal |
| issn | 1678-8060 |
| language | English |
| last_indexed | 2024-03-12T08:48:33Z |
| publisher | Fundação Oswaldo Cruz (FIOCRUZ) |
| record_format | Article |
| series | Memorias do Instituto Oswaldo Cruz |
| spelling | doaj.art-2a68d8814cae46f1a21abc049b64dfa32023-09-02T16:22:40ZengFundação Oswaldo Cruz (FIOCRUZ)Memorias do Instituto Oswaldo Cruz1678-8060010.1590/0074-02760160207S0074-02762016005023101Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targetsRenata Rachide NunesMarina dos Santos CostaBianca dos Reis SantosAmanda Luisa da FonsecaLorena Sales FerreiraRafael Cesar Russo ChagasAlisson Marques da SilvaFernando de Pilla VarottiAlex Gutterres TarantoThe 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.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762016005023101&lng=en&tlng=enPlasmodium falciparumplasmepsin-IIplasmepsin-IVfalcipain-IIPfATP6virtual screening |
| spellingShingle | Renata Rachide Nunes Marina dos Santos Costa Bianca dos Reis Santos Amanda Luisa da Fonseca Lorena Sales Ferreira Rafael Cesar Russo Chagas Alisson Marques da Silva Fernando de Pilla Varotti Alex Gutterres Taranto Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets Memorias do Instituto Oswaldo Cruz Plasmodium falciparum plasmepsin-II plasmepsin-IV falcipain-II PfATP6 virtual screening |
| title | 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_short | 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 |
| topic | Plasmodium falciparum plasmepsin-II plasmepsin-IV falcipain-II PfATP6 virtual screening |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762016005023101&lng=en&tlng=en |
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