title: Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets.
abstract: 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.
authors.affiliation: Universidade Federal de São João Del-Rei, Laboratório de Química Farmacêutica Medicinal, Divinópolis, MG, Brasil.|Universidade Federal de São João Del-Rei, Núcleo de Pesquisa em Química Biológica, Divinópolis, MG, Brasil.
authors.forename: Renata Rachide
authors.initials: RR
authors.lastname: Nunes
authors.affiliation: Centro Federal de Educação Tecnológica de Minas Gerais, Departamento de Informática, Gestão e Design, Divinópolis, MG, Brasil.
authors.forename: Marina Dos Santos
authors.initials: MD
authors.lastname: Costa
authors.affiliation: Centro Federal de Educação Tecnológica de Minas Gerais, Departamento de Informática, Gestão e Design, Divinópolis, MG, Brasil.
authors.forename: Bianca Dos Reis
authors.initials: BD
authors.lastname: Santos
authors.affiliation: Universidade Federal de São João Del-Rei, Núcleo de Pesquisa em Química Biológica, Divinópolis, MG, Brasil.
authors.forename: Amanda Luisa da
authors.initials: AL
authors.lastname: Fonseca
authors.affiliation: Universidade Federal de São João Del-Rei, Laboratório de Compostos Bioativos e Catalíticos, Divinópolis, MG, Brasil.
authors.forename: Lorena Sales
authors.initials: LS
authors.lastname: Ferreira
authors.affiliation: Universidade Federal de São João Del-Rei, Laboratório de Compostos Bioativos e Catalíticos, Divinópolis, MG, Brasil.
authors.forename: Rafael Cesar Russo
authors.initials: RC
authors.lastname: Chagas
authors.affiliation: Centro Federal de Educação Tecnológica de Minas Gerais, Departamento de Informática, Gestão e Design, Divinópolis, MG, Brasil.
authors.forename: Alisson Marques da
authors.initials: AM
authors.lastname: Silva
authors.affiliation: Universidade Federal de São João Del-Rei, Núcleo de Pesquisa em Química Biológica, Divinópolis, MG, Brasil.
authors.forename: Fernando de Pilla
authors.initials: FP
authors.lastname: Varotti
authors.affiliation: Universidade Federal de São João Del-Rei, Laboratório de Química Farmacêutica Medicinal, Divinópolis, MG, Brasil.
authors.forename: Alex Gutterres
authors.initials: AG
authors.lastname: Taranto
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy / Q000379:methods; D015800:Protozoan Proteins / Q000737:chemistry*; D019284:Thapsigargin / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D019284:Thapsigargin; D003546:Cysteine Endopeptidases; C416224:falcipain 2; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II