Integrated molecular docking, toxicity prediction, and molecular dynamics simulations studies to identify potential...

Malaria remains a life-threatening disease, and the emergence of drug-resistant Plasmodium falciparum highlights the urgent need for new antimalarial agents. Targeting enoyl-acyl carrier protein reductase (ENR), a key enzyme in the parasite's fatty acid synthesis pathway, offers a promising strategy for drug development. In this study, an integrated in silico approach was employed to identify potential ENR inhibitors from the Life Chemicals' Plasmodium Focused Library (7,900 compounds). Virtual screening was performed using Glide, followed by pharmacokinetic and toxicity prediction with pkCSM and ProTox 3.0, and molecular dynamics (MD) simulations with Desmond. The top five compounds-Cd3, Cd5, Cd7, Cd8, and Cd9-demonstrated favorable binding affinities and drug-like properties. Cd3 (docking score: -9.15) exhibited 100% intestinal absorption, favorable volume of distribution, moderate clearance, and higher predicted binding stability (RMSD < 3 Å) compared to Triclosan, the reference inhibitor. Toxicity predictions indicated potential hepatotoxicity, neurotoxicity, immunotoxicity, and respiratory toxicity for the top candidates, suggesting the need for structural optimization. Based on their overall pharmacokinetic and safety profiles, Cd3 and Cd5 are highlighted as the most promising candidates for further development. In vitro validation studies are recommended toconfirm binding affinities and antimalarial efficacy. This study demonstrates a cost-effective computational workflow for prioritizing ENR inhibitors, providing a foundation for the development of novel antimalarial agents.