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INTRODUCTION Amyloid-β accumulation, aberrant tau protein, neuroinflammation, and oxidative stress are some of the main pathogenic characteristics of Alzheimer's disease (AD), a degenerative illness characterized by cognitive deterioration. The majority of current AD therapies provide symptomatic alleviation with significant adverse effects, highlighting the urgent need for novel therapeutic approaches. OBJECTIVE This study examines nefopam, a centrally acting analgesic with NMDA antagonist and monoaminergic properties, as a potential treatment for AD using in silico methods like Network Pharmacology, Docking, and Molecular Dynamics Simulation studies. RESULTS Using network pharmacology, 90 molecular targets shared by the AD and nefopam pathways were identified. Following the selection of important hub proteins for further analysis, eight proteins with accessible 3D structures were put through molecular docking and MMGBSA computations. Nefopam demonstrated significant binding affinities, especially to 5HTR2A, GRIN1, 5HTR2C, SLC6A4, SLC6A3, and MAOB, whereas OPRM1 displayed weaker interactions, consistent with its lower MM-GBSA value (-37.04 kcal/mol) and docking score (-2.963). Molecular dynamics simulations of particular complexes over 100 ns revealed stable contacts and minimal structural changes for SLC6A3, SLC6A4, and 5HTR2A, suggesting strong and long-lasting binding. DISCUSSION The findings suggest that nefopam exhibits significant multi-target interactions with several proteins involved in AD pathogenesis, particularly those associated with neurotransmission, neuroprotection, and neuroinflammatory pathways. Its stable binding behavior and favorable interaction profiles support its potential role in modulating disease progression beyond symptomatic management. CONCLUSION Overall, this computational analysis confirms that nefopam can target multiple proteins linked to AD. These results show that more experimental research is necessary to validate nefopam's therapeutic potential and provide positive support for its repositioning in AD treatment.
