Background: Withania somnifera (WS), also referred to as Medhya Rasayana (nootropic or
rejuvenating), has traditionally been prescribed for various neurological ailments, including dementia.
Despite substantial evidence, pharmacological roles of WS, neither as nootropic nor as an antidementia
agent, are well-understood at the cellular and molecular levels.
Objectives: We aimed at elucidating the pharmacological action mechanisms of WS root constituents
against Alzheimer’s Disease (AD) pathology.
Methods: Various bioinformatics tools and resources, including DAVID, Cytoscape, NetworkAnalyst
and KEGG pathway database were employed to analyze the interaction of WS root bioactive molecules
with the protein targets of AD-associated cellular processes. We also used a molecular simulation
approach to validate the interaction of compounds with selected protein targets.
Results: Network analysis revealed that β-sitosterol, withaferin A, stigmasterol, withanolide A, and
withanolide D are the major constituents of WS root that primarily target the cellular pathways such as
PI3K/Akt signaling, neurotrophin signaling and toll-like receptor signaling and proteins such as Tropomyosin
receptor Kinase B (TrkB), Glycogen Synthase Kinase-3β (GSK-3β), Toll-Like Receptor 2/4
(TLR2/4), and β-secretase (BACE-1). Also, the in silico analysis further validated the interaction patterns
and binding affinity of the major WS compounds, particularly stigmasterol, withanolide A, withanolide
D and β-sitosterol with TrkB, GSK-3β, TLR2/4, and BACE-1.
Conclusion: The present findings demonstrate that stigmasterol, withanolide A, withanolide D and
β-sitosterol are the major metabolites that are responsible for the neuropharmacological action of WS
root against AD-associated pathobiology, and TrkB, GSK-3β, TLR2/4, and BACE-1 could be the potential