血管紧张素受体和内皮素受体双重受体拮抗剂药效团模型的研究(英文)  

Pharmacophore modeling of dual angiotensin Ⅱ and endothelin A receptor antagonists

作　　者：薛为哲[1] 吕炜 周智明[1] 王占黎 

机构地区：[1]北京理工大学化工与环境学院,北京100081 [2]创腾科技有限公司科技中心,上海200122

出　　处：《药学学报》2009年第9期1002-1008,共7页Acta Pharmaceutica Sinica

基　　金：supported by the Fundamental Research Foundation of Beijing Institute of Technology (1050050320704);the National Technological Project of the Manufacture and Innovation of Key New Drugs (2009ZX09103-143)

摘　　要：使用Catalyst软件中的HipHop模块分别产生了AT1受体拮抗剂和ETA受体拮抗剂的三维药效团模型。AT1受体拮抗剂最优药效团模型(Hypo-AT1-7)和ETA受体拮抗剂最优药效团模型(Hypo-ETA-1)均经过仔细的验证。两种药效团含有5个药效团特征[氢键受体(A)、脂肪族疏水(Z)、阴离子基团(N)、芳环(R)及芳环疏水(Y)],这5个特征是受体结合力的决定性因素。双重AT1和ETA受体拮抗剂可以分别与药效团模型Hypo-AT1-7和Hypo-ETA-1叠合。通过比较叠合最优模型Hypo-AT1-7和Hypo-ETA-1,发现两种模型不仅总结了两种拮抗剂的必要结构特征,并具有共同之处。这个研究结果将作为一个有效的工具用于设计和研究新型AT1和ETA双重受体拮抗剂及其结构关系。Three-dimensional pharmacophore models were generated for AT1 and ETA receptors based on highly selective AT1 and ETA antagonists using the program Catalyst/HipHop. Both the best pharmacophore model for selective AT1 antagonists （Hypo-AT1-7） and ETA antagonists （Hypo-ETA-1） were obtained through a careful validation process. All five features contained in Hypo-AT1-7 and Hypo-ETA-1 （hydrogen-bond acceptor （A）, hydrophobic aliphatic （Z）, negative ionizable （N）, ring aromatic （R）, and hydrophobic aromatic （Y）） seem to be essential for antagonists in terms of binding activity. Dual ATI and ETA receptor antagonists （DARAs） can map to both Hypo-AT1-7 and Hypo-ETA-1, separately. Comparison of Hypo-AT1-7 and Hypo-ETA-1, not only AT1 and ETA antagonist pharmacophore models consist of essential features necessary for compounds to be highly active and selective toward their corresponding receptor, but also have something in common. The results in this study will act as a valuable tool for designing and researching structural relationship of novel dual AT1 and ETA receptor antagonists.

关 键 词：AT1和ETA双重受体拮抗剂 血管紧张素Ⅱ 内皮素受体 药效团 

分 类 号：R979.1[医药卫生—药品] R914.2[医药卫生—药学]