The vascular endothelial growth factor （VEGF） and its receptor tyrosine kinases VEGFR-2 or kinase insertdomain receptor （KDR） have emerged as attractive targets for the design of novel anticancer agents. In the present work, molecular docking method combined with three dimensional quantitative structure-activity relationships （comparative molecular field analysis （CoMFA） and comparative molecular similarity indice analysis （CoMSIA）） to analyze the possible interactions between KDR and those derivatives which acted as selective inhibitors. The CoMFA and CoMSIA models gave a cross-validated coefficient Q2 of 0.713 and 0.549, non-cross-validated R2 values of 0.974 and 0.878, and predicted R2 values of 0.966 and 0.823, respectively. The 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. The information obtained from 3D-QSAR and docking studies were very helpful to design novel selective inhibitors of KDR with desired activity and good chemical property.
目的:为了定量解释12-LOX抑制剂活性和结构的关系,得到分子优化的方向。方法:从文献中得到一系列化合物,进行Topomer Co MFA研究。结果:模型具有良好统计学意义,分别为N=7,Q2=0.540,R2=0.952,F=162.3,SEE=0.14,Stderr=0.44,R2pred=5.52。结论:计算值与测量值的低偏差表示模型具有较强的预测能力,等势图和假设的结合模式提供了选择性的合理解释,这将指导进一步的研究。
The molecular docking by LigandFit docking of Discovery Studios 2.5 was employed to the three-dimensional quantitative structure-activity relationship（3D-QSAR） studies of biphenyl carboxylic acid MMP3 inhibitors.A significant correlation coefficient was obtained between dock scores and biological activities.Based on the optimal docking conformations,3D-HoVAIF was employed to the QSAR studies of 51 biphenyl carboxylic acid MMP-3 inhibitors.R2 and Q_CV2（leave-one-out,LOO） of the optimal 3D-HoVAIF-PLS model were 0.873 and 0.841 respectively.The conclusions obtained from the PLS analysis were in agreement with the docking results.
