5-羟色胺1A受体配体发现新思路: 基于受体的药效团

5-羟色胺1A受体配体发现新思路: 基于受体的药效团

杨志瑜, 吕炜, 田然, 金宏威, 曾慧慧^*

北京大学天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2008-11-24 修回日期:2009-05-10 出版日期:2009-06-15 发布日期:2009-06-15
通讯作者: 曾慧慧*

Insights into the discovery of new 5-HT1A receptor ligands: receptor based pharmacophore

Zhi-Yu Yang, Wei Lv, Ran Tian, Hong-Wei Jin, Hui-Hui Zeng^*

State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China

Received:2008-11-24 Revised:2009-05-10 Online:2009-06-15 Published:2009-06-15
Contact: Hui-Hui Zeng*

摘要/Abstract

摘要：

5-HT1A 是治疗焦虑症、抑郁症和疼痛等精神类疾病的重要靶点。近年来寻找5-HT1A 受体配体以及相关药物的发现, 一直是研究的热点。本文首先采用同源模建的方法构建了一个5-HT1A 受体模型, 并通过与MP349进行分子对接研究, 得到了一个可靠的受体-配体结合模式。在此基础上, 建立了一个基于受体的药效团模型, 该药效团模型包含许多配体和受体相互作用的重要特征; 并在后续的虚拟筛选实验中验证了这个药效团模型检验真正的5-HT1A 受体配体的能力。本研究结果可用于指导今后5-HT1A 配体的合成改造以及新的先导化合物的发现。

关键词: 5-HT1A受体, 同源模建, 分子对接, 药效团, 虚拟筛选

Abstract: 5-HT1A receptor is a crucial therapeutic target for the treatment of anxiety, depression, pain, etc. Design and preparation of potent 5-HT1Areceptor ligands for drug discovery has attracted extensive attention in the past few years. In this paper, a three dimensional model of human 5-HT1A receptor was constructed by means of homology modeling. And the docking of MP349 to the receptor suggested a reliable binding mode for 5-HT1A receptor ligand. Based on this ligand-receptor binding mode, an elaborate receptor structure based pharmacophore model was established, which revealed many important features responsible for ligand and 5-HT1A receptor interactions. A virtual screening experiment verified the ability of this pharmacophore model to discover true 5-HT1A receptor ligand. The results of this research would provide important information for further optimizations of 5-HT1A receptor ligands and guide related new lead discoveries.

Key words: 5-HT1A receptor, 5-HT1A receptor, Homology modeling, Homology modeling, Docking, Docking, Pharmacophore, Pharmacophore, Virtual screening, Virtual screening

中图分类号:

R916.1

Supporting:

^*Corresponding author. Tel./fax: 86-10-82802878;

e-mail: zenghh@bjmu.edu.cn

杨志瑜, 吕炜, 田然, 金宏威, 曾慧慧^*. 5-羟色胺1A受体配体发现新思路: 基于受体的药效团[J]. .

Zhi-Yu Yang, Wei Lv, Ran Tian, Hong-Wei Jin, Hui-Hui Zeng^*. Insights into the discovery of new 5-HT1A receptor ligands: receptor based pharmacophore[J]. .

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