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.

Low Ozone Concentrations Differentially Affect the Structural and Functional Features of Non-Activated and Activated Fibroblasts In Vitro

“…Human lung fibroblasts (WI-26, ATCC) were chosen for the present study as a suitable in vitro model previously used to investigate the effects of drugs on extracellular matrix deposition [ 81 ] and remodeling [ 82 ] as well as the response to various stimuli [ 83 , 84 , 85 ]. The fibroblasts were grown in Dulbecco’s modified Eagle’s medium supplemented with 10% ( v / v ) fetal bovine serum, 1% ( w / v ) glutamine, 100 U of penicillin and 100 μg/mL streptomycin (all reagents were purchased from Gibco, Walthem, MA, USA) at 37 °C in a 5% CO 2 humidified atmosphere.…”

Targeting Channels and Transporters in Protozoan Parasite Infections

“…It is discussed that iron II from heme when released from hemoglobin during degradation in the digestive vacuole chemically activates the artemisinins producing reactive oxygen species that damage proteins more or less specifically inside the mitochondria (Asawamahasakda et al, 1994 ; Moore et al, 2011 ) or at other sites in the cell including DNA as a target. Evidence further points to a P-type calcium ATPase, SERCA, or ATP6, at the sarcoplasmic endoplasmic reticulum as one of the affected proteins (Eckstein-Ludwig et al, 2003 ; Naik et al, 2011 ; Abiodun et al, 2013 ; Pulcini et al, 2013 ; Krishna et al, 2014 ; Nunes et al, 2016 ). However, there is a mismatch of artemisinin efficiency on the parasites and on heterologously expressed ATP6.…”

Decoys Selection in Benchmarking Datasets: Overview and Perspectives

“…In SBVS, tuned datasets should be used to identify the protocol, conformational sampling, and/or scoring methods that induces the best enrichment in active compounds (Allen et al, 2015 , 2017 ; Lacroix et al, 2016 ; Li et al, 2016 ; Nunes et al, 2016 ; Meirson et al, 2017 ). For instance, Allen et al ( 2015 , 2017 ) evaluated different scoring schemes using DUD-E generated decoys and successfully identified dual EFGR/BRD4 inhibitors.…”

“…An automated tool was made available online to generate decoys from user-supplied ligands using the same protocol ( http://decoys.docking.org ). The possibility to generate decoy sets for any target has been revealed successful and is now widely used by the scientific community (Lacroix et al, 2016 ; Nunes et al, 2016 ; Allen et al, 2017 ; Meirson et al, 2017 ).…”