人类腺苷受体A_3亚型拮抗剂的构效关系分析  

QSAR Analysis of Human Adenosine A_3 Receptor Antagonists

作　　者：乔康[1] 曾凌晓[1] 金宏威[1] 刘振明[1] 张亮仁[1] 

机构地区：[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

出　　处：《物理化学学报》2012年第6期1509-1519,共11页Acta Physico-Chimica Sinica

基　　金：国家自然科学基金(20972010);教育部博士点基金(20090001120049)资助项目~~

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.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.

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 

分 类 号：R96[医药卫生—药理学]