Repurposing of Neurological Drugs as Antimalarials: A Molecular Docking, MD Simulation, and MM/PBSA‐Guided Network Pharmacology Approach

Malaria caused by Plasmodium falciparum remains a major global health challenge due to resistance to frontline antimalarial agents. This study investigates repurposing of FDA‐approved neurological drugs against P. falciparum using an integrated computational pipeline involving molecular docking, MD simulations, molecular mechanics/Poisson‐Boltzmann surface area (MM/PBSA) binding free energy analysis, and network pharmacology. Docking results indicated that donepezil showed the highest binding affinity (−9.1 kcal/mol) with an estimated inhibition constant of 1.0 × 10 −5 nM, outperforming the reference drug mefloquine (−7.4 kcal/mol; Ki = 9.3 × 10 −5 nM), thereby identifying donepezil as the lead candidate. MD simulations demonstrated that the donepezil–protein complex remained structurally stable, exhibiting lower backbone root‐mean‐square deviation (RMSD), reduced residue fluctuations, a compact radius of gyration, and stable solvent‐accessible surface area compared with apo and mefloquine‐bound complexes. Essential dynamics analyses, including principal component analysis, free energy landscape, and dynamic cross‐correlation, indicated that donepezil stabilized protein conformational behavior. MM/PBSA calculations supported stronger binding of donepezil (−23.35 kcal/mol) compared with mefloquine (−18.24 kcal/mol). Network pharmacology identified 76 overlapping targets enriched in xenobiotic metabolism, inflammatory signaling, membrane‐associated processes, and heme‐binding pathways. Overall, this study highlights donepezil as a promising repurposed antimalarial candidate and demonstrates the value of integrated in silico approaches for antimalarial drug discovery.