物理化学学报 >> 2010, Vol. 26 >> Issue (09): 2549-2556.doi: 10.3866/PKU.WHXB20100844

生物物理化学 上一篇    下一篇

中药活性成分对血栓素A2受体抑制作用的分子模拟

刘海波1, 崔巍2, 徐峻3, 彭勇1, 周家驹4, 肖培根1   

  1. 1. 中国医学科学院北京协和医学院药用植物研究所, 北京100193;
    2. 中国科学院研究生院化学与化学工程学院, 北京100049;
    3. 中山大学药学院, 广州510275;
    4. 中国科学院过程工程研究所,北京100190
  • 收稿日期:2010-02-10 修回日期:2010-05-05 发布日期:2010-09-02
  • 通讯作者: 徐峻, 彭勇 E-mail:junxu@biochemomes.com;ypeng@implad.ac.cn
  • 基金资助:

    国家自然科学基金重点项目(30530860)资助

Molecular Simulations of the Inhibition of Active Components in Traditional ChineseMedicine on the Thromboxane A2 Receptor

LIU Hai-Bo1, CUI Wei2, XU Jun3, PENG Yong1, ZHOU Jia-Ju4, XIAO Pei-Gen1   

  1. 1. Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100193, P. R. China;
    2. College of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049, P. R. China;
    3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China;
    4. Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P. R. China)
  • Received:2010-02-10 Revised:2010-05-05 Published:2010-09-02
  • Contact: XU Jun, PENG Yong E-mail:junxu@biochemomes.com;ypeng@implad.ac.cn
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (30530860).

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摘要：

中药中黄酮类化合物和白藜芦醇等活性成分对血栓素A2 受体具有抑制作用, 但具体机理不详. 本研究 通过同源模建方法, 以墨鱼视紫红质蛋白为模板, 构建血栓素A2 受体的蛋白质结构模型. 并使用分子对接方法 研究中药活性成分白藜芦醇和芹菜苷元与血栓素A2 受体模型的作用方式, 据此建立药效团模型, 筛选其他潜 在的血栓素A2受体抑制剂. 结果表明:白藜芦醇等中药活性成分能与血栓素A2 受体活性口袋中的残基发生氢 键作用, 结合方式与血栓素相似. 血栓素与Ser201、Leu198、Arg295 和Thr298 发生氢键作用, 白藜芦醇等活性成 分与Ser201、Leu198 和Arg295发生氢键作用. 建立的药效团模型由7 个药效元素以及排斥性空间元素组成, 经 测试对高活性的血栓素A2 受体抑制剂有比较好的选择性. 使用该药效团模型对中药天然产物数据库进行筛选, 命中了一批可能具有血栓素粤圆受体抑制作用的活性化合物. 其中一些已经报道有抑制血小板凝聚活性. 本研 究表明血栓素A2 受体可能是活血化瘀类中药的一个潜在的靶点.

关键词: 中药, 药物靶标, 血栓素受体, 活血

Abstract:

Some natural products from traditional Chinese medicine (TCM) such as flavones and resveratrol have been reported to have thromboxane A2 receptor (TP) inhibiting activity.We investigated a possible inhibition mechanism by a homology model of TP, which was built based on the crystal structure of squid rhodopsin. After that, docking methods were used to investigate the binding modes of resveratrol and apigenin in the active pocket of TP. Furthermore, a three- dimensional pharmacophore model was generated for screening other potential natural TP inhibitors. The results indicate that resveratrol and apigenin bind to the active site of TP similar to the way that thromboxane A2 binds to Ser201, Leu198, Arg295, and Thr298. The former three key residues can form hydrogen bonds with the inhibitors. The pharmacophore model consisted of seven features and a set of volume spheres, which has been proven to be efficient in identifying compounds with high TP inhibition activity. In this way, a set of potential TP inhibitors were screened from a natural product database. Some of them were reported to have platelet aggregation inhibiting activities. This research indicates that TP could be an important target of TCMdrugs with blood circulation activation effects.

Key words: Traditional Chinese medicine, Drug target, Thromboxane A2 receptor, Blood circulation activating