Molecular Docking and Dynamics-Based Repurposing of Thalidomide and Lenalidomide for GSK-3β Inhibition in AD

Glycogen synthase kinase-3 beta (GSK-3β) is a key serine/threonine protein kinase involved in several neural processes. Its overactivity contributes to the pathogenesis of Alzheimer's disease (AD) through tau protein hyperphosphorylation and amyloid-beta (Aβ) accumulation. Thalidomide and lenalidomide, originally developed as anticancer drugs, have shown potential inhibitory effects on GSK-3β in vitro. In this study, we repurposed these compounds to design novel GSK-3β inhibitors for AD therapy using computational methods.

The 3D structure of GSK-3β (PDB ID: 1Q41) was prepared using the Biovia Discovery Studio. A library of 100 ligands (50 each from thalidomide and lenalidomide) was designed using ChemDraw, followed by molecular docking using PyRX. Ligands with better binding affinities than source compounds were further evaluated for pharmacokinetic and ADMET parameters using SwissADME and ProTox II tools. Molecular dynamics (MD) simulations of the best ligand-protein complex were performed using Desmond for 100 ns to analyze the stability of interactions.

Seventy-five percent of the designed ligands exhibited stronger binding affinities compared to the source drugs. ADMET analysis identified LS9 as the most promising lead molecule, attributed to its high binding affinity (-11.3 kcal/mol), favorable drug-likeness, and lack of toxicity. Molecular dynamics simulation confirmed the stability of the LS9-GSK-3β complex, with RMSD values ranging from approximately 2.4 to 2.6 Å and consistent protein-ligand interactions.

This study demonstrates that structure-based ligand modification of repurposed drugs can yield candidates with significantly improved GSK-3β binding and pharmacological profiles. Compared to previous inhibitors, our ligands showed superior docking scores and better drug-likeness.

LS9 is a promising GSK-3β inhibitor with potential for AD therapy. Its robust binding, safety profile, and MD stability warrant further investigations.