Design, Bio-evaluation and Molecular Dynamics Simulation of Novel GSK-3β Inhibitors

Glycogen synthase kinase 3 beta (GSK-3 beta) is considered as a promising drug target for the treatment of Alzheimer's disease (AD). In the present study, two compound libraries were selected for virtual screening based on pharmacophore models of GSK-3 beta to discover new inhibitors. Nine potential hits were retained for biological investigation and four of these compounds showed GSK-3 beta inhibitory activity (with the IC50 values in sub-micromolar range on GSK-3 beta). Compounds 6 and 9 have good safety. They do not have any significant in vitro cytotoxicity against PC12 and SH-SY5Y neuroblastoma cells at concentrations up to 90 mu M. Based on the inhibitory activity and druggability properties, compound 8 is the preferred molecule, and it is a promising lead for the development of the GSK-3 beta inhibitors for reducing the abnormal hyperphosphorylation of tau protein and relieving AD.