Inhibitors of Plasmepsin X Plasmodium falciparum: Structure-based pharmacophore generation and molecular dynamics simulation

Abstract

Malaria is a life-threatening disease caused by Plasmodium parasites, which are transmitted to humans through infected female Anopheles mosquitoes. Over the past few decades, antimalarial resistance has posed one of the most important health challenges around the globe. To counteract the increased resistance to artemisinin combination therapy (ACT), the discovery of effective new antimalarial medicines is required at the moment. Plasmepsin X (PMX), an aspartic protease, is unravelled recently for playing an important role in egress and invasion of intraerythrocytic parasites by activating subtilisin-like protease 1. Therefore, the current study is centralized on PMX for in-silico identification of effective drugs. Structure based pharmacophore generation and virtual screening filtered out 47 candidates from almost 108 million entries catered in CHEMBL, PubChem, and ZINC databases. Five best hits were chosen based on docking scores. 1 µs molecular dynamics of homologue PMX and its complexes with the shortlisted five hit molecules and a known inhibitor 49c elucidated the stability of the complexes. Consistent with docking, the binding free energy estimated using MM-PBSA method recognized hits 1 (−144.4 kJ/mol) and 2 (−130.1 kJ/mol) the best inhibitors among all hits and the known inhibitor 49c (−68.7 kJ/mol). The new inhibitors can be put forward for further in-vivo studies as an antimalarial drug based on the comprehensive analyses reported herein.