Inhibitory potential of polyphenolic stilbene derivatives with Glycogen Synthase Kinase-3β (GSK-3β) for Alzheimer's disease: Computational and SAR insights

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder. Beta-amyloid plaques and tau protein tangles emerge in the brain as pathological hallmarks of AD. One important enzyme involved in tau phosphorylation, Glycogen Synthase Kinase-3β (GSK-3β), has become a viable therapeutic target for AD. A new approach to AD intervention is provided by polyphenolic stilbene derivatives, which are well-known for their wide range of biological activities and show strong inhibitory capability against GSK-3β. This work uses computational methods, such as molecular docking, binding energy analysis, and structure-activity relationship (SAR) insights, to investigate the inhibitory action of polyphenolic stilbene derivatives. Molecular docking and MD-simulation of the best docked Piceid (C12) compounds were used to analyze the backbone stability and conformational binding affinity with the target protein GSK-3β. The SAR of Piceid and GSK-3β protein was specifically examined as the primary candidate target. Furthermore, binding free energy (MMGBSA), drug-likeness and toxicity, medicinal chemistry parameters were investigated in support to be lead compound for drug discovery. The molecular docking binding affinity of Piceid (C12) compound was found -8.8 Kcal/mol which is higher than GSK-3β inhibitor standard compound Laduviglusib (C18) has binding energy -8.7 Kcal/mol. These results imply that piceid has potential as an AD treatment because to its favorable interaction profile and high binding affinity.