Steered molecular dynamics and free-energy analysis of withanolide unbinding from tau kinases TTBK1 and GSK-3β

MM-GBSA analyses complemented these findings and identified van der Waals interactions as the primary contributors to protein-ligand complex stabilisation. Collectively, the results provide detailed molecular insights into ligand recognition, binding stability and dissociation energetics in tau-associated kinases. These findings highlight withanolidebased scaffolds as promising candidates for structure guided optimisation and the development of kinase targeted therapeutics against tau-related neurodegenerative disorders.</p> <p>Communicated by Kavitha J.</p> <p>Multi-panel figure illustrating molecular structures, tau phosphorylation, brain pathology, and withanolide binding energetics.This figure presents a multi-panel analysis titled "MD-SMD-US Investigation of Withanolide Inhibition on Kinases driving TAU Hyperphosphorylation".

On the left, ribbon diagrams depict TTBK1 and GSK3ß kinases, followed by a schematic showing phosphorylation pathways and a brain MRI panel illustrating tau aggregation. The right side details computational findings: binding diagrams of withanolides, a 3D energy landscape plot, and graphs depicting protein-ligand interactions over time, culminating in a graphic on the unbinding energetics of Withanolide A from TTBK1.</p>