马来酰胺类糖原合成酶激酶-3β抑制剂的分子对接和三维定量构效关系

摘要

通过分子对接和三维定量构效关系(3D-QSAR)两种方法来确定两类马来酰胺类的糖原合成酶激酶-3β(GSK-3β)抑制剂的结合方式.首先,用分子对接确定抑制剂与GSK-3β的结合模式及其相互作用;然后用比较分子力场分析法(CoMFA)与比较分子相似性指数分析法(CoMSIA)对48个化合物做三维定量构效关系的分析.两种方法得出的交互验证回归系数分别为0.669(CoMFA)和0.683(CoMSIA),证明该模型具有很好的统计相关性,同时也说明该模型具有较高的预测能力.根据该模型提供的信息,设计出9个预测性较好的分子.%Molecular docking and three-dimensional quantitative structure-activity relationship(3D-QSAR)approaches were used to characterize the binding features of two different series of maleimide glycogen synthase kinase-3β(GSK-3β)inhibitors,3-(indol-3-yl)-4-(1H-indazol-3-yl)maleimides and 3-(benzofuran-3-yl)-4-(indol-3-yl)maleimides.First,molecular docking was applied to characterize the binding modes and interactions between ligands and GSK-3β.A comparative molecular field analysis(CoMFA)and comparative molecular similarity indice analysis (CoMSIA)were then employed to develop 3D-QSAR models of 48 compounds.The excellent predictive capability of these 3D-QSAR models were validated by a satisfactory correlation coefficient using leave-one-out cross-validation q2 values(q2 values were 0.669 and 0.683 for CoMFA and CoMSIA,respectively).Satisfactory predictions on externally tested compounds also validated the models.Using the 3D-QSAR models,9 molecules were designed with predicted good binding affinities in terms of molecular docking score and they also had good predicted values for inhibition.