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Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening

文献类型：期刊论文

作者Zhou, Qingtong1; Guo, Wanjing2,3; Dai, Antao2,4; Cai, Xiaoqing2,4; Vass, Marton5; de Graaf, Chris5; Shui, Wenqing6,7; Zhao, Suwen6,7; Yang, Dehua2,3,4; Wang, Ming-Wei1,2,3,4,7
刊名BIOMOLECULES
出版日期2021-07-01
卷号11期号:7页码:14
关键词GLP-1R virtual screening allosteric modulator drug discovery molecular docking
DOI10.3390/biom11070929
通讯作者Zhao, Suwen(zhaosw@shanghaitech.edu.cn) ; Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.
WOS关键词GLUCAGON-LIKE PEPTIDE-1 ; HIGH-THROUGHPUT ; FORCE-FIELD ; RECEPTOR ; PROTEIN ; DOCKING ; ACTIVATION ; MECHANISM ; FRAGMENT ; EFFICACY
资助项目National Key Research and Development Program of China[2018YFA0507000] ; National Key Research and Development Program of China[2016YFC0905900] ; National Natural Science Foundation of China[21704064] ; National Natural Science Foundation of China[81573479] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[31971178] ; Shanghai Science & Technology Development Fund[16ZR1407100] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; National Mega R&D Program for Drug Discovery grants[2018ZX09711002-002-005] ; National Mega R&D Program for Drug Discovery grants[2018ZX09735-001]
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者MDPI
WOS记录号WOS:000676655900001
源URL[http://119.78.100.183/handle/2S10ELR8/296732]  
专题中国科学院上海药物研究所
通讯作者Zhao, Suwen; Yang, Dehua; Wang, Ming-Wei
作者单位1.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Vrije Univ Amsterdam, Fac Sci, Amsterdam Inst Mol Med & Syst, Div Med Chem, NL-1081 Amsterdam, Netherlands
6.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
7.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Qingtong,Guo, Wanjing,Dai, Antao,et al. Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening[J]. BIOMOLECULES,2021,11(7):14.
APA Zhou, Qingtong.,Guo, Wanjing.,Dai, Antao.,Cai, Xiaoqing.,Vass, Marton.,...&Wang, Ming-Wei.(2021).Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening.BIOMOLECULES,11(7),14.
MLA Zhou, Qingtong,et al."Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening".BIOMOLECULES 11.7(2021):14.

入库方式： OAI收割

来源：上海药物研究所

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