4-苄基哌啶类拮抗剂选择性识别hCCR3的分子模拟

Molecular Modeling Studies on the Selectivity of 4-Benzylpiperidine Antagonists for hCCR3

以牛视网膜紫质X射线衍射晶体结构为模板,参考定位突变实验数据,采用配体支持同源模建(Ligand-supported homology modeling)方法构建了拮抗剂键合(Antagonist-bound)的人类趋化因子受体hCCR3和hCCR1的三维结构模型.将一系列1,4-二取代哌啶类拮抗剂分别对接进优化后的hCCR3和hCCR1模型中,以配体在hCCR3中的结合自由能理论值对-lgIC50值进行线性回归,确定性系数r2为0.94.分析对接结果发现,配体主要通过疏水芳香作用与hCCR3结合,而4-苄基哌啶类拮抗剂对hCCR3产生选择性的主要原因在于配体的哌啶环与hCCR3中Tyr255(TM7)的苯酚侧链产生面对面的范德华作用,而且hCCR3中处于结合口袋的EL2区的疏水性也为拮抗剂对hCCR3的选择性做出了贡献.

The ＂antagonist-bound＂ three-dimensional models of the hCCR3 and hCCR1 receptors were constructed by homology modeling,using the X-ray structure of bovine rhodopsin as the template,and refined with molecular modeling and molecular dynamics（MM/MD） methods.We also carried out an automated docking of several 1,4-disubstituted piperidine antagonists into the hCCR3 and hCCR1 model.The binding hypothesis and the reliability of the hCCR3 model were confirmed by the reasonable correlation between the estimated binding free energy and the experimental-lgIC50 values（r^2=0.94）.The docking results reveal that the face-to-face van der Waals interaction between piperidine ring and Tyr255 plays an important role on the selectivity of 4-phenzylpiperidine antagonists to hCCR3.Simultaneously,the more hydrophobic of the EL2 in hCCR3 is favorable for the selectivity of 4-phenzylpiperidine antagonists.