Targeting Mitochondrial Drp1 Dynamics in Neurodegenerative Diseases: A Comprehensive Drug Design Approach Using AutoDock Vina‐GPU, DFT, and Molecular Dynamics Simulations

Abstract Dysregulation of mitochondrial fission has been implicated in the pathogenesis of several neurodegenerative disorders. Dynamin‐related protein 1 (Drp1) plays a pivotal role in mitochondrial fission, leading to neuronal degeneration. Therefore, inhibiting Drp1 has been regarded as a novel strategy for treating such disorders. In this regard, 1.6 million compounds from the ChemDiv database were screened against mitochondrial Drp1. RDKit was used for duplicates removal, random sampling, Tanimoto similarity, Butina clustering, and filters like PAINS, Lipinski's rule of five, and Veber's rule. A total of 9996 molecules were subjected to molecular docking using AutoDock Vina‐GPU 2.1, followed by further refined docking of 10 molecules using AutoDock4. Compounds D5780117, C7970438, C5930523, E7810109, and IB078933 were identified as promising hits and underwent molecular dynamics simulations in complex with Drp1. The simulated systems were analyzed in terms of RMSD, RMSF, RoG, SASA, free energy landscape analysis, principal component analysis, cluster analysis, and binding energy estimations using MM/GB(PB)SA methods. Moreover, density functional theory calculations were performed to investigate the electronic characteristics of the ligands. The results will guide further experimental studies to explore potential compounds for treating neurodegenerative illnesses targeting the mitochondrial Drp1 protein.