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Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets
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
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.
Keywords
Plasmodium falciparum; plasmepsin-II; plasmepsin-IV; falcipain-II; PfATP6; virtual screening
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