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化学学报
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化学学报 ›› 2005, Vol. 63 ›› Issue (23): 2131-2136. 上一篇    下一篇

研究论文

酪氨酸蛋白磷酸酯酶1B抑制剂的分子对接和三维定量构效关系研究

周梅1, 章威2, 成元华3, 计明娟1, 徐筱杰2   

  1. 1. 中国科学院研究生院化学与化学工程学院, 北京, 100049;
    2. 北京大学化学与分子工程学院, 北京, 100871;
    3. 北京工业大学环境与能源工程学院, 北京, 100022
  • 投稿日期:2005-03-28 修回日期:2005-06-28 发布日期:2014-02-14
  • 通讯作者: 计明娟,E-mail:jmj@gscas.ac.cn;Tel:010-88256326. E-mail:jmj@gscas.ac.cn
  • 基金资助:

    国家自然科学基金(No.20373089);中国科学院研究生院启动基金(No.M3004)资助项目

Molecular Docking and 3D-QSAR Studies on Protein Tyrosine Phosphatase 1B Inhibitors

ZHOU Mei1, ZHANG Wei2, CHENG Yuan-Hua3, JI Ming-Juan1, XU Xiao-Jie2   

  1. 1. College of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049;
    2. College of Chemistry and Molecular Engineering, Peking University, Beijing 100871;
    3. College of Environmental and Energy Engineering, Beijing University of Technology, Beijing 100022
  • Received:2005-03-28 Revised:2005-06-28 Published:2014-02-14

PDF

432

被引次数

14

用一种柔性分子对接方法(FlexX)将12个2-草酰胺苯甲酸类抑制剂和酪氨酸蛋白磷酸酯酶(PTP1B)活性口袋进行分子对接,对接程序预测的抑制剂和酶之间的相互作用能与抑制活性之间有很好的相关性(非线性相关系数R2达0.859),这说明对接结果可以比较准确地预测抑制剂和PTP1B之间的结合模式.然后,将33个同类抑制剂的骨架叠合在分子对接预测的结合构象上,用比较分子力场分析方法(CoMFA)对其进行三维定量活性构效关系研究,得到的CoMFA模型具有很好的统计相关性(交互验证回归系数q2为0.650),并可以准确地预测测试集6个化合物的活性(平均标准偏差为0.177).同时,由CoMFA模型得出的抑制剂改造信息与用FlexX预测的结合模式是一致的,进一步证明我们预测的结合模式是正确的.为研究这类抑制剂和PTP1B的结合模式及对抑制剂进行结构改造提供了信息.

关键词: 酪氨酸蛋白磷酸酯酶, 分子对接, 三维定量构效关系, 比较分子力场分析方法

Here a molecular docking and 3D-QSAR study is reported on a series of 2-(oxalic mono-amido)benzoic acid (OBA) inhibitors and protein tyrosine phosphatase 1B (PTP1B). Firstly, a flexible docking method (FlexX) was used to place 12 OBA inhibitors into the active site of PTP1B. The predicted binding affinities of the molecules were found to be linearly relevant to their experimental activities (pKi, non-cross-validated R2=0.859). After that, 33 OBA inhibitors were fixed into the predicted binding con-formation, and were studied using CoMFA method. The resulting CoMFA model (cross-validated q2=0.650) could predict the activity of 6 molecules in the test set within a mean unsigned error of 0.177, and match the characters of our binding mode perfectly. The discovered binding mode could provide hints to further modification of inhibitors.

Key words: protein tyrosine phosphatase, molecular docking, 3D-QSAR, CoMFA