Multi-target therapeutic potential of Neem (Azadirachta indica) phytochemicals in Alzheimer's disease: an integrative network pharmacology and molecular dynamics simulation approach.

Alzheimer' s disease (AD) remains a significant challenge in neurological research, with limited treatments available to halt or reverse its progression. This study utilizes an in-silico approach to explore the therapeutic potential of Neem (Azadirachta indica)-derived phytochemicals in targeting key AD-associated proteins. We screened 286 bioactive compounds, selecting 9 with favorable ADME profiles and blood-brain barrier permeability. A compound-target complex network was built to retrieve hub genes through topological analysis. GO and KEGG analyses provided biological insights into target functions. Molecular docking assessed compound binding affinities, while molecular dynamics simulations analyzed stability and interaction details through RMSD, RMSF, radius of gyration, SASA, and PCA. Network analysis highlighted ESR1, HSP90AA1, SRC, HIF1A and EP300 as key hub genes within the AD-related compound-target network, suggesting critical regulatory roles. KEGG pathway analysis emphasized Neem compounds roles in mitigating cell death, amyloid accumulation, apoptosis, and synaptic dysfunction, suggesting their therapeutic potential in AD. Subsequent molecular docking revealed high binding affinities of Nimolinin and Isomargolonone with AD-associated proteins, particularly HSP 90-alpha, Src kinase, and HIF-1α. These compounds demonstrated strong hydrogen bonding and hydrophobic interactions, showing promise for stabilizing pathological protein conformations in AD. MD simulations validated interaction stability, with RMSD and RMSF analyses confirming consistent binding and minimal fluctuations. Structural integrity, solvent accessibility, and PCA further supported stable binding. This integrative in-silico study identifies Nimolinin and Isomargolonone as promising multi-target compounds with strong affinities for key AD-related proteins and pathways. These findings provide a foundation for experimental validation (Enzyme-Linked Immunosorbent Assay and western blotting) further could offer novel therapies for AD. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00434-1.