化学学报 ›› 2012, Vol. 70 ›› Issue (06): 796-802.DOI: 10.6023/A1109071 上一篇    下一篇

研究论文

AT1 受体的中药活性成分筛选模型及其作用机理研究

吴琼a, 康宏b, 王欢欢a, 高军b,c, 朱瑞新a,b, 康廷国a   

  1. a 辽宁中医药大学药学院 大连 116600;
    b 同济大学生命科学与技术学院 上海 200092;
    c 上海海事大学信息工程学院 上海 201306
  • 收稿日期:2011-09-07 修回日期:2011-11-28 出版日期:2012-03-28 发布日期:2011-12-19
  • 通讯作者: 朱瑞新
  • 基金资助:

    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.

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

Wu Qionga, Kang Hongb, Wang Huanhuana, Gao Junb,c, Zhu Ruixina,b, Kang Tingguoa   

  1. a School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China;
    b School of Life Sciences and Technology, Tongji University, Shanghai 200092, China;
    c School of Information Engineering, Shanghai Maritime University, Shanghai 201306, China
  • Received:2011-09-07 Revised:2011-11-28 Online:2012-03-28 Published:2011-12-19
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 30976611), the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 2010-0072120050).

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.

关键词: AT1 受体, 中药活性成分, 同源模建, 分子对接, 分子机理

The traditional Chinese medicine (TCM) has a significant effect on the treatment of cardiovascular diseases and some has been widely used in clinical therapy, such as Uncaria, Astragalus and Motherwort. 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 telangiectasia, 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, Ser105 by hydrogen bonds, and the mechanism was similar with receptor AT1 antagonists which bound with the residues His183, Lys199, His256, Gln257,Ser105, Ser109, Tyr113, Asn200. In this study, the mechanism of some TCM active compounds was explained on molecular level, which provided a foundation for further screening and rational design of AT1R antagonists from traditional Chinese medicine.

Key words: angiotensin Ⅱ type 1 receptor, active components in traditional Chinese medicine, homology model, molecular docking, molecular mechanism