物理化学学报 >> 2009, Vol. 25 >> Issue (05): 890-896.doi: 10.3866/PKU.WHXB20090409

研究论文 上一篇    下一篇

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

魏卓 张怀 崔巍 计明娟   

  1. 中国科学院研究生院化学与化学工程学院, 北京 100049; 中国科学院研究生院计算地球动力学重点实验室, 北京 100049
  • 收稿日期:2008-10-20 修回日期:2008-12-04 发布日期:2009-05-04
  • 通讯作者: 计明娟 E-mail:jmj@gucas.ac.cn

Molecular Docking and 3D-QSAR on Maleimide Derivatives as Glycogen Synthase Kinase-3β Inhibitors

WEI Zhuo, ZHANG Huai, CUI Wei, JI Ming-Juan   

  1. College of Chemistry and Chemical Engineering, Graduate University of the Chinese Academy of Sciences, Beijing 100049, P. R. China; Laboratory of Computational Geodynamics, Graduate University of the Chinese Academy of Sciences, Beijing 100049, P. R. China
  • Received:2008-10-20 Revised:2008-12-04 Published:2009-05-04
  • Contact: JI Ming-Juan E-mail:jmj@gucas.ac.cn

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个预测活性较好的分子.

关键词: 糖原合成酶激酶3β, 三维定量构效关系, 比较分子力场分析法, 比较分子相似性指数分析法, 分子对接

Abstract:

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.

Key words: GSK-3β, 3D-QSAR, CoMFA, CoMSIA, Molecular docking

MSC2000: 

  • O641