AT_1受体的中药活性成分筛选模型及其作用机理研究  

AT1R-based Virtual Screening Model for Bioactive Components from Traditional Chinese Medicines and Its Mechanism Study

作　　者：吴琼[1] 康宏[2] 王欢欢[1] 高军[2,3] 朱瑞新[1,2] 康廷国[1] 

机构地区：[1]辽宁中医药大学药学院,大连116600 [2]同济大学生命科学与技术学院,上海200092 [3]上海海事大学信息工程学院,上海201306

出　　处：《化学学报》2012年第6期796-802,共7页Acta Chimica Sinica

基　　金：国家自然科学基金(No.30976611);高等学校博士学科点专项科研基金(No.2010-0072120050)资助项目~~

摘　　要：传统中药对治疗心血管类疾病疗效显著,例如钩藤、黄芪、益母草等在临床应用广泛.现代药理研究表明钩藤碱可以降压;黄芪中毛蕊异黄酮能舒张血管平滑肌、保护心脑血管;益母草碱可扩张微血管,改善血液流变异常,但它们分子层面作用机制尚不明确.首先以牛视紫红质蛋白为模板,模建出心血管疾病主要靶点AT1受体的三维结构.然后将AT1受体拮抗剂和中药活性成分与受体模型结合的作用方式进行了对比研究,据此提出了中药活性成分治疗心血管疾病的作用机理,并建立了AT1受体的中药活性成分筛选模型.结果表明:黄芪毛蕊异黄酮等中药活性成分能与AT1受体活性口袋中的残基发生氢键作用,结合方式与AT1受体拮抗剂相似.每一种AT1受体拮抗剂均与His183,Lys199,His256,Gln257,Ser105,Ser109,Tyr113,Asn200中多个发生氢键作用;黄芪毛蕊异黄酮与Try113,Lys199,Gln257,Ser105发生氢键作用.本研究从分子层面上阐释了一些中药活性小分子的治病机理,为进一步挖掘中药资源,研究AT1受体相关的心脑血管类药物,合理设计和筛选AT1受体的拮抗剂提供重要依据.The traditional Chinese medicine （TCM） has a significant effect on the treatment of cardiovas- cular diseases and some has been widely used in clinical therapy, such as Uncaria, Astragalus and Mother wort. The previous research found that Rhy could lower blood pressure; Calycosin in Astragalus could relax vascular smooth muscle, protect cardiovascular and cerebrovascular; and Leonurine could increase te langiectasia, improve abnormity of hemorheology; however, the mechanism of these was not clear. Here, the structure of receptor AT1, which was the main target of cardiovascular diseases, has been modeled based on the crystal structure of bovine rhodopsin; meanwhile, the interaction of receptor AT1 antagonists to receptor AT1 was compared with that of the active compounds in TCMs. The results indicated that Calycosin and Leonurine could bind the residues Try113, Lys199, Gln257, Serl05 by hydrogen bonds, and the mechanism was similar with receptor AT1 antagonists which bound with the residues His183, Lys 199, His256, Gin257,Serl05, Ser109, Tyr113, Asn200. In this study, the mechanism of some TCM active compounds was ex plained on molecular level, which provided a foundation for further screening and rational design of AT1R antagonists from traditional Chinese medicine.

关 键 词：AT1受体 中药活性成分 同源模建 分子对接 分子机理 

分 类 号：R285[医药卫生—中药学]