TLR7激动剂的三维药效团模型研究

doi:10.5246/jcps.2013.02.020

TLR7激动剂的三维药效团模型研究

齐世光, 于慧, 金宏威, 王占黎^*

1. 包头医学院第二附属医院, 内蒙古包头 014030
2. 北京大学医学部天然药物及仿生药物国家重点实验室, 北京 100191
3. 包头医学院第一附属医院, 内蒙古包头 014010

收稿日期:2012-10-24 修回日期:2012-01-03 出版日期:2013-03-18 发布日期:2013-03-18
通讯作者: 王占黎*

Three-dimensional common-feature hypotheses for Toll-like receptor 7 agonists

Shiguang Qi, Hui Yu, Hongwei Jin, Zhanli Wang^*

1. The Second Affiliated Hospital, Baotou Medical College, Baotou 014030, China
2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
3. The First Affiliated Hospital, Baotou Medical College, Baotou 014010, China

Received:2012-10-24 Revised:2012-01-03 Online:2013-03-18 Published:2013-03-18
Contact: Zhanli Wang*

摘要/Abstract

摘要：

本研究选择了5个TLR7激动剂作为训练集, 使用Discovery Studio软件包构建了TLR7激动剂的药效团模型。最终获得的最优药效团模型Hypo2由一个氢键受体、一个氢键给体和两个疏水中心组成, 对训练集和测试集具有较好的预测能力。此外, 将Hypo2作为提问结构搜索由79个不同活性的TLR7激动剂 (0.2-5000 nM) 组成的化合物库, 该模型能有效将数据库中高活性的TLR7激动剂识别为目标化合物。分子对接研究进一步验证了该药效团模型的合理性。本研究获得的TLR7激动剂药效团模型有助于发现新型TLR7激动剂。

关键词: Toll样受体7, 激动剂, 药效团模型, 分子对接

Abstract:

Toll-like receptor 7 (TLR7), the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional (3D) pharmacophore models were constructed from a set of 5 TLR7 agonists. Among the 10 common-featured models generated by program Discovery Studio/HipHop, a hypothesis (Hypo2) including one hydrogen-bond donor (D), one hydrogen-bond acceptor (A), and two hydrophobic (H) features was considered to be important in evaluating the ligands with TLR7 agonistic activity. The obtained pharmacophore model was further validated using a set of test molecules and the Catalyst TLR7-agonist-subset database. Hypo2 has been shown to identify a range of highly potent TLR7 agonists. Finally, the obtained pharmacophore was further validated using docking studies. Taken together, this model can be utilized as a guide for future studies to design the structurally novel TLR7 agonists.

Key words: Toll-like receptor 7, Agonist, Common-feature hypothesis, Molecular docking

中图分类号:

R916

Supporting: Foundation items: National Natural Science Foundation of China (Grant No. 20902068), Natural Science Foundation of Inner Mongolia Autonomous Region, China (Grant No. 2011BS1201) and Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region, China.
^¶These authors made equal contribution to this work.
^*Corresponding author. Tel.: 86-472-2178195;

齐世光, 于慧, 金宏威, 王占黎^*. TLR7激动剂的三维药效团模型研究[J]. , DOI: 10.5246/jcps.2013.02.020.

Shiguang Qi, Hui Yu, Hongwei Jin, Zhanli Wang^*. Three-dimensional common-feature hypotheses for Toll-like receptor 7 agonists [J]. , DOI: 10.5246/jcps.2013.02.020.

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