eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2025-09-30 18 3 2070 2082 10.13005/bpj/3238 67254 article Magesh Mohan 1 Renukadevi Jeyavelkumaran 1 Vijayakumar Balakrishnan 2 Sanjay Valliappan 1 Department of Pharmaceutical Chemistry, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Kerala University of Health Sciences, Palakkad, India Cofilin is crucial for the maintenance of neuronal architecture, synaptic plasticity, and intracellular transport. The dimerization of cofilin under oxidative stress contributes to the formation of cofilin-actin rods, which severely interfere with synaptic signaling, axonal transport, and intracellular trafficking. Such pathological changes are hallmarks of various neurodegenerative diseases. This study aimed at the identification of small-molecule inhibitors targeting cofilin dimerization, which could restore its monomeric, actin-severing state. Eighteen candidate compounds were screened using molecular docking and molecular dynamics simulations to assess their potential to disrupt the dimerization interface. Asiaticoside, Actinorhodin, and Granatin A demonstrated the most favorable binding affinities, with Asiaticoside emerging as the strongest inhibitor (-7.3 kcal/mol). Derived from Bacopa monnieri (Brahmi), Asiaticoside displayed stable binding to critical dimerization residues, as confirmed by molecular dynamics simulations. These simulations showed a stable protein-ligand complex with minimal structural fluctuations, a consistent hydrogen bond network, and strong electrostatic and hydrophobic interactions. This work highlights the therapeutic potential for targeting cofilin dimerization to restore actin filament dynamics and ameliorate neurodegenerative disease-associated cytoskeletal dysfunction. The overall findings suggest Asiaticoside to be a promising lead compound, with experimental validation and optimization being necessary to enhance the translational application in the treatment of neurodegenerative disorders. https://biomedpharmajournal.org/vol18no3/molecular-modelling-study-of-cofilin-dimer-inhibitors-in-cognitive-decline/ Asiaticoside Cofilin dimer inhibitors Cognitive decline GROMACS MD simulation