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

Lyu, Weiping; Li, Qihang; Li, Qi; Chen, Ying; Wang, Yingming; Tang, Tongzhong; Feng, Feng; Chi, Heng; Li, Yuan; Liu, Wenyuan; Sun, Haopeng

Glycogen synthase kinase 3 beta (GSK-3β) 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-3β to discover new inhibitors. Nine potential hits were retained for biological investigation and four of these compounds showed GSK-3β inhibitory activity (with the IC50 values in sub-micromolar range on GSK-3β). 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 μM. 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-3β inhibitors for reducing the abnormal hyperphosphorylation of tau protein and relieving AD.