2026-10-10T05:38:27Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34021770 2026-09-29T07:07:21Z category_1 category_4 category_915 category_12 category_13 category_14 category_15 category_873 category_734 category_64 category_135 portal_87 item_type_3 month_year_09_2026

Steered molecular dynamics and free-energy analysis of withanolide unbinding from tau kinases TTBK1 and GSK-3β Kavitha J. (25135836) Sindhu K. S. (25135839) George M. (25135842) Dhiya Francis (25135845) Abi T. G. (25135848) Biophysics Biochemistry Physical Sciences not elsewhere classified Cell Biology Genetics Molecular Biology Neuroscience Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Cancer Computational Biology Alzheimer’s tau kinases withanolides steered molecular dynamics umbrella sampling <p>Tau hyperphosphorylation is identified as a critical process in microtubule destabilisation, neurodegeneration and synaptic dysfunction. Considering the kinases involved in this process, Tau Tubulin Kinase 1 (TTBK1) and Glycogen Synthase Kinase-3β (GSK-3β) have emerged as potential therapeutic targets. Here, we employed an integrated molecular simulation approach to investigate the binding thermodynamics and unbinding mechanisms of five Ashwagandha-derived withanolides sominone, withanolide A, withanolide D, withanone and withaferin A targeting TTBK1 and GSK-3β. Principal component analysis and free-energy landscape mapping identified distinct conformational basins and representative bound-state structures for each protein-ligand complex. Steered molecular dynamics simulations, followed by umbrella sampling and weighted histogram analysis, were used to characterise ligand dissociation pathways and determine the potentials of mean force. The calculated binding free energies ranged from −9 to −13 kcal mol⁻¹, indicating favourable ligand binding affinity for both kinases. 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> 2026-09-29T07:07:21Z Dataset Dataset 10.6084/m9.figshare.34021770.v1 https://figshare.com/articles/dataset/Steered_molecular_dynamics_and_free-energy_analysis_of_withanolide_unbinding_from_tau_kinases_TTBK1_and_GSK-3_/34021770 CC BY 4.0