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. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, 72388, Sakaka, Saudi Arabia Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan The authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.

If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Alsrhani, A., Riaz, S. & Khan, M.U.

Virtual screening of Withania somnifera phytochemicals identifies scopoletin and linoleic acid as predicted dual-target AChE/BACE1 candidates for alzheimer’s disease. Sci Rep (2026). https://doi.org/10.1038/s41598-026-71874-8 DOI: https://doi.org/10.1038/s41598-026-71874-8