Using Topomer CoMFA and Surflex-dock to analyze 3D-QSAR of GSK-3β inhibitors and their mechanism of action
YaFei ZENG, Guixue Wang, Bozhi Shi, Guizhao Liang, YiQiang SHAO, Y. Liu, YueTing LI, Kan ZHONG, DanDan HUANG · Scientia Sinica Chimica · 2013
Overexpression of glycogen synthase kinase 3β (GSK-3β) in human's nerve cells will lead to hyperphosphorylation of tau protein, which results in the occurrence of Alzheimer's disease (AD). In this work we designed new GSK-3β inhibitors using 3D-QSAR and studied their mechanism of action. A 3D-QSAR model of 49 maleimide derivations as GSK-3β inhibitors was constructed using Topomer CoMFA. A total of 25 molecules were used to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting, cross validation and external validation were 0.928, 0.790 and 0.725, respectively. Topomer search was employed to select R group in ZINC molecular database; as a result, a total of 28 new compounds with potential higher activity than other inhibitors were designed. Then, we explored the interaction mode between the new inhibitors and the GSK-3β acceptor using Surflex-dock. The results suggest that Topomer CoMFA combining with Surflex-dock could be effectively applied to design anti-AD drugs, and the new designed molecules could provide new candidates for the discovery of leading compounds of GSK-3β inhibitors.