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

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.

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

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 R~2=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 q~2=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.