分子对接技术用于马来酰亚胺类GSK-3α抑制剂的作用特征分析

Using docking to investigate mechanism of action of GSK-3α inhibitors

糖原合酶激酶-3α(GSK-3α)是治疗阿尔兹海默症(AD)的关键靶点之一.采用基于R基团的搜索组合分子对接研究了GSK-3α抑制剂的作用特征.以45个马来酰亚胺类GSK-3α抑制剂分子为训练集,采用Topomer CoMFA建立3D-QSAR模型,其拟合与留一法交互验证的复相关系数和标准差分别为r2=0.797,SD=0.210,q2cv=0.611,SDcv=0.280,对22个测试集样本外部预测的复相关系数与标准差分别为r2pred=0.703,SDpred=0.213.以Topomer Search搜索技术设计了25个理论上具有更高活性的新型分子.分子对接对比研究表明,新设计的分子与建模样本同GSK-3α的作用位点具有类似的作用特征,且与对比文献一致.该研究为AD治疗的分子设计与研发提供了新的思路.

Glycogen synthase kinase-3α（GSK-3α） is one of the key targets against Alzheimer′s disease（AD）.We use R-groups search and molecular docking to investigate mechanism of action of new inhibitors of GSK-3α.A total of 45 3-anilino-4-phenylmaleimide derivatives were used to develop a 3D-QSAR model based on Topomer CoMFA,and 22 test samples were used to validate the predictive ability of the model obtained.The multiple correlation coefficient and the standard deviation of fitting modeling,leave one out cross validation,and external validation were as follows：r2=0.797,SD=0.210,q2cv=0.611,SDcv=0.280,r2pred=0.703,and SDpred=0.213.We design 25 new compounds with high activity in theory using research.Through comparison,the results of molecular docking show that the interaction between new designed molecules and GSK-3α is well agreement with the experimental conclusion of other reports.This study provides a new approach for drug design and development toward AD treatment.