内皮素受体A拮抗剂药效团模型的建立

Pharmacophore Model Construction of Endothelins A Receptor Antagonist

目的:构建内皮素受体A(Endothelins A Receptor,ETA)的拮抗剂药效团模型,用以搜索中草药数据库,寻找中药ETA受体拮抗剂。方法:以对鼠主动脉平滑肌细胞的内皮素受体A有抑制作用的36个化合物为研究对象,分别利用HipHop定性药效团模型和HypoGen定量药效团模型构建方法,建立ETA受体拮抗剂药效团模型,利用数据库搜索方法对药效团模型进行优劣评判。并用所获得的最优定性和定量药效团模型对中药化学成分数据库进行筛选。结果:获得最优定性药效团模型具有以下6个特征:1个芳环基团、1个负离子基团、3个疏水基团及1个氢键受体,其综合评判指数CAI值为103.94。最优定量药效团模型具有以下6个特征:1个芳环基团、1个负离子基团、2个疏水基团、1个氢键受体以及1个排除体积,其综合评判指数CAI值为45.96,表明所构建动物模型具有一定的可靠性,且利用定量药效团模型筛选中药化学成分数据库命中16个化学成分。结论:本文所构建的定性和定量药效团模型筛选效率较高,可分别开展活性化合物筛选和活性预测研究,有助于指导发现中药ETA受体拮抗剂。

This study was aimed to construct the pharmacophore models of endothelins A receptor antagonist in the application of screening traditional Chinese medicine（TCM） database for novel ETA Receptor antagonists.Qualitative and quantitative hypotheses were generated by HipHop and HypoGen separately on the basis of 36 compounds with antagonistic action on Endothelins A Receptor expressed in the aortic smooth muscle cells of rats.Database searching method was used to evaluate the generated hypotheses.The optimum hypotheses were used to search TCM database.The results showed that optimum qualitative hypothesis is with six features,which were one aromatic ring,one hydrogen-bond acceptors,one negative ionizable group and three hydrophobic groups,and the CAI value of 103.94.The optimum quantitative hypothesis is with six features,which were one aromatic ring,one hydrogen-bond acceptor,one negative ionizable group,two hydrophobic groups and one exclusive volume,and the CAI value of 45.96.Sixteen compounds from TCM were found in the database searching with the quantitative hypothesis.It was concluded that the pharmacophores are reliable and can be used to screen database for novel ETA inhibitors.The qualitative and quantitative hypothesis can be used to screen database for active compounds and to predict the activity respectively.