中国新药杂志

胰高血糖素样肽-1受体的分子动力学模拟研究

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都宵晓 ¹^,² , 孟凡翠 ² , 刘巍 ² , 汤立达 ²

中国新药杂志 | 实验研究 2021,30(8): 732-739

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中国新药杂志 |实验研究 2021 , 30 (8) : 732 -739

胰高血糖素样肽-1受体的分子动力学模拟研究

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都宵晓¹^,², 孟凡翠², 刘巍², 汤立达²

作者信息

¹天津医科大学药学院，天津　300070

²天津药物研究院天津市新药设计与发现重点实验室，天津　300450

通讯作者:

汤立达，男，研究员，主要从事新药设计与评价研究。联系电话：（022）23006950，E-mail：tangld@tjipr.com。

作者简介:

都宵晓，女，硕士研究生，主要从事药理学研究。联系电话：（022）23006858，E-mail：dxx021396@163.com。

Molecular dynamics simulation study of glucagon-like peptide-1 receptor

Xiao-xiao DU¹^,², Fan-cui MENG², Wei LIU², Li-da TANG²

Affiliations

¹Pharmacy College, Tianjin Medical University, Tianjin 300070, China

²Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300450, China

出版时间: 2021-04-30

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摘要

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目的：

采用分子动力学模拟方法研究胰高血糖素样肽-1受体（GLP-1R）的激活机制。

方法：

分别构建激活态和失活态的GLP-1R结构，置于棕榈酰-油酰-卵磷脂（POPC）双层膜内，进行50 ns的分子动力学模拟，比较不同体系的构象并进行氢键、能量、主成分等性质分析。

结果：

结果表明失活态的胞外域整体倒向跨膜区，激活态和失活态的胞内第三loop（ICL3）构象差异明显，可见ICL3在GLP-1R的激活中扮演着重要角色。氢键和能量分析结果均表明胰高血糖素样肽-1（GLP-1）的His7*，Glu9*和Asp15*在与GLP-1R的结合中起着较为重要的作用。

结论：

分子动力学模拟作为辅助手段可用于研究GLP-1R构象变化对其自身激活的影响以及GLP-1与受体结合时的激活机制，为以GLP-1R为靶点的药物研发提供一定的理论指导。

关键词

胰高血糖素样肽-1受体 / 激活态 / 失活态 / 分子动力学 / 药物

Abstract

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Objective:

To investigate the activation mechanism of glucagon-like peptide-1 receptor (GLP-1R) by molecular dynamics method.

Methods:

The active and inactive states of GLP-1R were constructed and embedded in a palmitoyl oleoyl phosphatidyl choline (POPC) bilayer. Molecular dynamics simulations were carried out on each system for 50 ns. Conformations of active and inactive states were compared, and hydrogen bond analysis, energy analysis and principal component analysis etc. were performed.

Results:

Conformation analysis showed that the N-terminal ectodomain of GLP-1R moved to the transmembrane domain in inactive state. The third intracellular loop (ICL3) was different between active and inactive states of GLP-1R, suggesting that ICL3 played a significant role in the activation of GLP-1R. The outcomes of hydrogen bond analysis and energy analysis indicated that His7*, Glu9* and Asp15* of GLP-1 were important in the binding of GLP-1R.

Conclusion:

Molecular dynamics method can be used as a supplementary tool to study the effects of GLP-1R conformational changes on its own activation and the activation mechanism of GLP-1 binding to receptors, providing theoretical guidance for the development of drugs targeting GLP-1R.

Key words

glucagon-like peptide-1 receptor / active state / inactive state / molecular dynamics / drugs

引用本文

都宵晓, 孟凡翠, 刘巍, 汤立达. 胰高血糖素样肽-1受体的分子动力学模拟研究. 中国新药杂志, 2021 , 30 (8) : 732 -739 .

Xiao-xiao DU, Fan-cui MENG, Wei LIU, Li-da TANG. Molecular dynamics simulation study of glucagon-like peptide-1 receptor[J]. Chinese Journal of New Drugs, 2021 , 30 (8) : 732 -739 .

基金

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天津市新药创制科技重大专项(18ZXXYSY00040)

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2021年第30卷第8期

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首发时间：2026-10-28
出版时间：2021-04-30

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录用日期：2020-11-30

基金

天津市新药创制科技重大专项(18ZXXYSY00040)

作者信息

¹天津医科大学药学院，天津　300070

²天津药物研究院天津市新药设计与发现重点实验室，天津　300450

通讯作者:

汤立达，男，研究员，主要从事新药设计与评价研究。联系电话：（022）23006950，E-mail：tangld@tjipr.com。

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https://castjournals.cast.org.cn/joweb/zgxyzz/CN/1322245680911987284

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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