| 药效团模型法寻找M1受体激动剂 |
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| 引用本文： | 高广涛,牛彦,王栋,雷小平,胡应和.药效团模型法寻找M1受体激动剂[J].中国药学,2008,17(1):75-78. |
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| 作者姓名： | 高广涛 牛彦 王栋 雷小平 胡应和 |
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| 作者单位： | 高广涛（北京大学药学院,北京,100083;天然药物及仿生药物国家重点实验室,北京,100083）;牛彦（北京大学药学院,北京,100083;天然药物及仿生药物国家重点实验室,北京,100083）;王栋（华东师范大学,脑功能基因组学研究所,上海,200062）;雷小平（北京大学药学院,北京,100083;天然药物及仿生药物国家重点实验室,北京,100083）;胡应和（华东师范大学,脑功能基因组学研究所,上海,200062） |
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| 基金项目： | 国家自然科学基金
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面向21世纪教育振兴行动计划(985计划) |
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| 摘 要： | 寻找新的M1受体激动剂先导化合物。在M1受体三维结构未知的情况下，利用距离比较法（DISCO）将10个结构特征具有代表性的M1受体激动剂的分子构象进行叠合，建立了可能的药效团模型，初步验证了该模型的可靠性。利用该模型对ACD-SC数据库进行虚拟筛选，购买了22个与药效团叠合较好、与已知M1受体激动剂结构类型不同的化合物，并对其进行活性测定。结果发现了一个具有M1受体激动活性的化合物，其EC50为4．90μmol／L，最大响应倍数为10．0，值得进行更深入研究。
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| 关 键 词： | 距离比较法 M1受体激动剂 药效团模型 虚拟筛选 阿尔茨海默症 |
| 文章编号： | 1003-1057(2008)1-75-04 |
| 修稿时间： | 2007年2月15日 |
New lead discovery for novel M1 agonists: pharmacophore model based on DISCO computation and virtual screening |
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| Guang-Tao Gao,Yan Niu,Dong Wang,Xiao-Ping Lei,Ying-He Hu.New lead discovery for novel M1 agonists: pharmacophore model based on DISCO computation and virtual screening[J].Journal of Chinese Pharmaceutical Sciences,2008,17(1):75-78. |
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| Authors: | Guang-Tao Gao Yan Niu Dong Wang Xiao-Ping Lei Ying-He Hu |
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| Institution: | Guang-Tao Gao, Yan Niu, Dong Wang, Xiao-Ping Lei and Ying-He Hu( 1. School of Pharmaceutical Sciences, Peking University, Beijing 100083; 2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083; 3. Institute of Brain Functional Genomics, East China Normal University, Shanghai 200062) |
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| Abstract: | To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the three-dimensional structure of M1 receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds （ACD-SC） to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M1 agonists were purchased in order to evaluate their M1 receptor agonist activity. One of them shows M1 receptor agonist activity with EC50 of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M1 agonists. |
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| Keywords: | DISCO M1 agonists Pharmaeophore model Virtual screening Alzheimer's disease |
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