Multi-targeted approach via apigenin-7-O-glucoside for therapeutic intervention of Tau phosphorylating kinases in Alzheimer's disease.

Alzheimer's disease (AD) is one of the leading tauopathies in which several kinases phosphorylate Tau in response to Aβ oligomers, inflammation, calcium dysregulation, oxidative stress, mitochondrial dysfunction, or disruption of the key signaling pathways. Tau is phosphorylated by Ser/Thr kinases such as GSK3β, CDK5, MAPK14, and MARK2, as well as Tyr kinases like Fyn. Given the large crosstalk among these kinases, targeting one of these kinases is ineffective in treating tauopathies such as AD, highlighting the need for a multi-targeted approach. In this study, we targeted key kinases involved in Tau hyperphosphorylation using compounds derived from the medicinal plant Berberis lycium (B.ly.), which is reported to have anti-inflammatory, autophagy, and antioxidant properties. We employed virtual screening, ADMET evaluation, PASS analysis, DFT, molecular dynamics (MD) simulation, and MM/PBSA studies to assess the interaction of B.ly. compounds with CDK5, Fyn, GSK3β, MARK2, and MAPK14. Apigenin-7-O-glucoside (A7OG) was selected for its strong binding affinity within the ATP-binding pockets of these kinases. MD simulations demonstrated that A7OG exhibited promising inhibitory effects on CDK5, Fyn, MARK2, and MAPK14, with minimal fluctuation in its interaction with GSK3β. MM/PBSA analyses indicated stable binding energies for all the kinase-A7OG complexes. Our multitargeted investigations revealed that A7OG could be a promising molecule implicated in modulating tau hyperphosphorylating kinases that could lead to the development of therapeutic interventions in AD treatment. The online version contains supplementary material available at 10.1007/s13205-025-04413-3.