Investigations Through In Silico Molecular Modelling Against Falcipain‐2 in Search of Potent Anti‐Malarial Agents

Abstract Malaria remains a major global health concern, exacerbated by the increasing resistance of Plasmodium falciparum to existing anti‐malarial drugs. This growing challenge necessitates the urgent discovery of novel therapeutic agents targeting unexplored biological pathways. Falcipain‐2, a cysteine protease involved in hemoglobin metabolism during the erythrocytic stage, has emerged as the promising and key drug target. The current state of resistance to malaria treatments has made it imperative to find new anti‐malarial drugs using in silico tools driven by computer aided drug design. A virtual screening of 91,001 ligands from the Asinex Elite Synergy 2021–02 library has been performed using AutoDock Vina, yielding 20 hits with superior binding affinities (−10.0 to −9.7 kcal/mol) compared to the reference inhibitor, E64 (−5.8 kcal/mol). Further evaluation of their pharmacokinetic and toxicity profiles confirmed their favorable ADMET properties, suggesting high oral bioavailability and drug‐likeness. The stability of the top two identified compounds in complex with Falcipain‐2 was further validated through molecular dynamics (MD) simulations over 100 ns using GROMACS. These findings highlight the efficacy of computational strategies in accelerating anti‐malarial drug discovery and provide a strong foundation for the development of next‐generation therapeutics targeting drug‐resistant malaria.