Integrated System Pharmacology and Analysis Elucidating Neuropharmacological Actions of in the Treatment of Alzheimer's Disease.

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 druggable targets.