Virtual screening of Withania somnifera phytochemicals identifies scopoletin and linoleic acid as predicted dual-target AChE/BACE1 candidates for alzheimer’s disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by interlinked pathological processes, including cholinergic deficit and amyloid-β accumulation, limiting the efficacy of single-target therapies. Multitarget-directed ligands capable of simultaneously modulating acetylcholinesterase (AChE) and β-secretase 1 (BACE1) offer a promising but underexplored strategy, particularly from natural product sources. Although the withanolides of Withania somnifera have been extensively studied for neuroprotection, its non-withanolide phytochemical fraction remains largely unexplored as a source of dual-target anti-AD agents. Here, from 129 initially retrieved non-withanolide phytochemical entries, duplicate removal across plant parts yielded 80 unique compounds, of which 76 returned valid SwissADME outputs; these compounds, derived from W. somnifera were evaluated using an integrated in silico pipeline comprising ADMET and toxicity profiling, molecular docking against AChE (PDB: 7E3H) and BACE1 (PDB: 7F1D), PASS-based bioactivity prediction, BioTransformer metabolite profiling, and 100-ns molecular dynamics simulations, with donepezil as the reference inhibitor. Twelve compounds satisfied pharmacokinetic filtering criteria, and this screening identified scopoletin and linoleic acid as the leading dual-target candidates, showing computationally predicted binding affinities toward AChE (− 7.7 and − 7.9 kcal/mol) and BACE1 (− 5.2 and − 5.8 kcal/mol) respectively, together with favorable blood–brain barrier permeability and low predicted toxicity. Molecular dynamics analysis further showed that the AChE-linoleic acid complex maintained conformational stability comparable to the AChE-donepezil reference complex over the full 100-ns trajectory, supporting a physically stable binding mode. These findings identify scopoletin and linoleic acid as predicted dual-target AChE/BACE1 candidates from W. somnifera , offering a computational foundation for their experimental validation as multitarget neuroprotective candidates against Alzheimer's disease.