药效团模型法寻找M1受体激动剂

药效团模型法寻找M₁受体激动剂

高广涛, 牛彦, 王栋, 雷小平^*, 胡应和^**

1.北京大学药学院, 北京 100083;
2.天然药物及仿生药物国家重点实验室, 北京 100083;
3.华东师范大学脑功能基因组学研究所, 上海 200062

收稿日期:2007-02-15 修回日期:2008-01-10 出版日期:2008-03-15 发布日期:2008-03-15
通讯作者: 雷小平*, 胡应和**

New lead discovery for novel M1 agonists: pharmacophore model based on DISCO computation and virtual screening

Guang-Tao Gao, Yan Niu, Dong Wang, Xiao-Ping Lei^*, 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

Received:2007-02-15 Revised:2008-01-10 Online:2008-03-15 Published:2008-03-15
Contact: Xiao-Ping Lei*, Ying-He Hu**

摘要/Abstract

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4.90 μmol/L, 最大响应倍数为10.0, 值得进行更深入研究。

关键词: 距离比较法, 距离比较法, 距离比较法, M1受体激动剂, M1受体激动剂, M1受体激动剂, 药效团模型, 药效团模型, 药效团模型, 虚拟筛选, 虚拟筛选, 虚拟筛选, 阿尔茨海默症, 阿尔茨海默症, 阿尔茨海默症

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 M₁receptor 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.

Key words: DISCO, DISCO, M1 agonists, M1 agonists, Pharmacophore model, Pharmacophore model, Virtual screening, Virtual screening, Alzheimer's disease, Alzheimer's disease

中图分类号:

R916.1

Supporting: Foundation item: National Natural Science Foundation of China (Grant No. 30271538) and 985 program, Ministry of Education of China.
^*Corresponding authors. ^*Tel.: 86-10-82801505;
^**Tel.: 86-21-62232789

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]. .

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]. .

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药效团模型法寻找M₁受体激动剂

New lead discovery for novel M1 agonists: pharmacophore model based on DISCO computation and virtual screening

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