Exploring the Molecular Basis of Q_obc₁ Complex Inhibitors Activity to Find Novel Antimalarials Hits

Abstract

Cytochrome bc1 complex is a crucial element in the mitochondrial respiratory chain, being indispensable for the survival of several species of Plasmodia that cause malaria and, therefore, it is a promising target for antimalarial drug development. We report a molecular docking study building on the most recently obtained X-ray structure of the Saccharomyces cerevisiae bc1 complex (PDB code: 3CX5) using several reported inhibitors with experimentally determined IC50 values against the Plasmodium falciparum bc1 complex. We produced a molecular docking model that correlated the calculated binding free energy with the experimental inhibitory activity of each compound. This Qo model was used to search the drug-like database included in the MOE package for novel potential bc1 complex inhibitors. Twenty three compounds were chosen to be tested for their antimalarial activity and four of these compounds demonstrated activity against the chloroquine-resistant W2 strain of P. falciparum. The most active compounds were also active against the atovaquone-resistant P. falciparum FCR3 strain and S. cerevisiae. Our study suggests the validity of the yeast bc1 complex structure as a model for the discovery of new antimalarial hits.

Computational fishing of new DNA methyltransferase inhibitors from natural products

“…4. The correlation analysis indicated the inhibition of DNMT1 activity follows a highly dependence with calculated binding scores for these compounds (r= 0.83, p value <0.0001; for binding affinity vs logIC50, r= 0.65, p value <0.0001; for Total score vs logIC50), with correlation coefficients comparable to those reported in other studies for these validations[56,59,60,73] as shown inFig. 4a and Fig.…”

“…The feasibility of NPs to work as inhibitors of DNMTs was evaluated with two docking programs frequently used for virtual screening, AutoDock Vina [54][55][56] and Surflex-Dock [57]; which are based on different score functions to evaluate the binding mode of a ligand onto a receptor. United/All-atoms force fields with AMBER charges.…”

“…The biological information consisted of the half maximal inhibitory concentration (µM, IC50) values for DNMT1 activity, as reported for these chemicals in PubChem BioAssay (AID: 602386, Dose response confirmation of DNMT1 inhibitors in a Fluorescent Molecular Beacon assay). Correlation analysis to establish the relationships between binding scores on DNMT1, generated by AutoDock Vina and Surflex-Dock, and experimental biological data (LogIC50)[56,60] for DNMTis were calculated using STATISTICA 8.0 software[48].…”

In Silico Screening

“…Several comparative studies have been published over time, highlighting the strengths and weaknesses of each software tool. For example, AutoDock 4.0 was recently used to discover novel antiplasmodial compounds as potential cytochrome bc 1 inhibitor starting points for medicinal chemistry optimization [95]. For example, AutoDock 4.0 was recently used to discover novel antiplasmodial compounds as potential cytochrome bc 1 inhibitor starting points for medicinal chemistry optimization [95].…”

Insights into the phylogenetic relationship and drug targets of Babesia infective to small ruminants from its mitochondrial genomes

“…Inhibitors of cytochrome bc1 complex may be divided into two types that act on Qi and Qo sites according to the binding site. Some studies suggest that yeast bc1 complex structure could be used as a model for discovering new antimalarial drugs [24,25]. The mutations in the cytochrome b (cob) gene have been found to be the molecular basis of drug resistance [25][26][27][28].…”