物理化学学报 >> 2012, Vol. 28 >> Issue (06): 1509-1519.doi: 10.3866/PKU.WHXB201203272

生物物理化学 上一篇    下一篇

人类腺苷受体A3亚型拮抗剂的构效关系分析

乔康, 曾凌晓, 金宏威, 刘振明, 张亮仁   

  1. 北京大学药学院, 天然药物及仿生药物国家重点实验室, 北京 100191
  • 收稿日期:2012-02-22 修回日期:2012-03-27 发布日期:2012-05-17
  • 通讯作者: 金宏威,张亮仁 E-mail:liangren@bjmu.edu.cn; jinhw@bjmu.edu.cn
  • 基金资助:

    国家自然科学基金(20972010)和教育部博士点基金(20090001120049)资助项目

QSAR Analysis of Human Adenosine A3 Receptor Antagonists

QIAO Kang, ZENG Ling-Xiao, JIN Hong-Wei, LIU Zhen-Ming, ZHANG Liang-Ren   

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China
  • Received:2012-02-22 Revised:2012-03-27 Published:2012-05-17
  • Contact: JIN Hong-Wei, ZHANG Liang-Ren E-mail:liangren@bjmu.edu.cn; jinhw@bjmu.edu.cn
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (20972010) and Doctoral Fund of Ministry of Education of China (20090001120049).

摘要: 构建人类腺苷受体A3亚型药效团模型和三维蛋白结构模型用于作用模式研究. 以18 个来源于文献具有腺苷受体A3亚型拮抗活性的化合物作为训练集, 使用HypoGen方法构建药效团模型. 通过同源模建和分子动力学模拟构建了人类腺苷受体A3亚型的三维蛋白模型, 并利用PROCHECK方法评估该模型的合理性, 对所得的结构使用分子对接程序进行作用模式分析, 药效团模型和同源模建结果相互匹配较好. 使用新药效团模型对MDL药物数据库(MDDR)中包含的约120000 个化合物进行虚拟筛选, 得到了8 个候选化合物, 用于进一步的生物学评价和活性测定. 本工作对于人类腺苷受体A3亚型拮抗剂的设计和抗哮喘药物的研发具有一定的理论指导和应用价值.

关键词: 药效团模型, 同源模建, 分子对接, 虚拟筛选, 人类腺苷受体A3亚型, 拮抗剂

Abstract: Ligand-based and receptor-based methods were implemented together to investigate the binding modes of human adenosine A3 antagonists. First, pharmacophore models were developed using the HypoGen program with a training set of 18 diverse human adenosine A3 receptor antagonists from literature. Meanwhile, the three-dimensional structure of A3 receptor was modeled by homology modeling and molecular dynamics, and validated by PROCHECK. Molecular docking was conducted further to investigate receptor-ligand interactions. The pharmacophore model and homology models of A3 receptor matched well, allowing some important information to be obtained. One of the new pharmacophore models was used to screen the MDL drug database report (MDDR) including about 120000 compounds. As a result, eight candidate compounds that can be used for biological evaluation were discovered. These findings are important for the development and discovery of novel selective A3 antagonists and antiasthmatic compounds.

Key words: Pharmacophore modeling, Homology modeling, Molecular docking, Virtual screening, Human adenosine A3 receptor, Antagonists

MSC2000: 

  • O641