Antimalarial Flavonoid-Glycoside from Acacia pennata with Inhibitory Potential Against PfDHFR-TS: An In-silico Study

Abstract

Drug resistance, toxicity, and adverse effects of current antimalarial drugs have mandated the need to search for newer antimalarial agents. The present study aims to identify promising flavonoid-glycosides (FGs) from Acacia pennata as possible antimalarial agents effective against PfDHFR-TS (PDB ID: 3DGA) by in-silico studies. The co-crystal inhibitor (RJ1) of PfDHFR-TS was used as the reference standard compound. A compound library of 17 FGs reported to be isolated from A. pennata was prepared and subjected to molecular docking simulation studies. PyRx 0.8 and AutoDock Vina revealed Pinocembrin-7-O-β-D-glucopyranoside (FG17) as the best PfDHFR-TS inhibitor with a binding affinity of -10.4 kcal/mol and -10.8 kcal/mol, respectively. In both methods, FG17 has a better binding affinity than the co-crystal inhibitor, RJ1 (-7.9 kcal/mol). The docking protocols were validated by RMSD calculation with Discovery Studio Visualizer software (2020). FG17 interacted with amino acids ALA16, LEU40, SER167, GLY41, GLY44, MET55, PHE58, ILE112, LEU119, GLY166, and TYR170 at the active binding site of PfDHFR-TS. Further, FG17 was computed as a non-toxic, bioavailable, synthetically accessible compound and a better enzyme inhibitor than RJ1. Hence, we conclude that FG17 may be used as a lead scaffold to design antimalarial agents against PfDHFR-TS in the future.