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Affinity Mass Spectrometry-Based Fragment Screening Identified a New Negative Allosteric Modulator of the Adenosine A(2A) Receptor Targeting the Sodium Ion Pocket

文献类型：期刊论文

作者Lu, Yan2,3,4; Liu, Hongyue2,3,4; Yang, Dehua5,6; Zhong, Li5,6; Xin, Ye2,3,4; Zhao, Suwen2,3; Wang, Ming-Wei1,3,4,5,6,7; Zhou, Qingtong7; Shui, Wenqing2,3
刊名ACS CHEMICAL BIOLOGY
出版日期2021-06-18
卷号16期号:6页码:991-1002
ISSN号1554-8929
DOI10.1021/acschembio.0c00899
通讯作者Wang, Ming-Wei(mwwang@simm.ac.cn) ; Zhou, Qingtong(zhouqt@fudan.edu.cn) ; Shui, Wenqing(shuiwq@shanghaitech.edu.cn)
英文摘要Allosteric ligands provide new opportunities to modulate G protein-coupled receptor (GPCR) function and present therapeutic benefits over orthosteric molecules. Negative allosteric modulators (NAMs) can inhibit the activation of a receptor and downstream signal transduction. Screening NAMs for a GPCR target is particularly challenging because of the difficulty in distinguishing NAMs from antagonists bound to the orthosteric site as they both show inhibitory effects in receptor signaling assays. Here we report an affinity mass spectrometry (MS)-based approach tailored to screening potential NAMs of a GPCR target especially from fragment libraries. Compared to regular surface plasmon resonance or NMR-based methods for fragment screening, our approach features a reduction of the protein and compound consumption by 2-4 orders of magnitude and an increase in the data acquisition speed by 2-3 orders of magnitude. Our affinity MS-based fragment screening led to the identification of a new NAM of the adenosine A(2A) receptor (A(2A)AR) bearing an unprecedented azetidine moiety predicted to occupy the allosteric sodium binding site. Molecular dynamics simulations, ligand structure-activity relationship (SAR) studies, and in-solution NMR analyses further revealed the unique binding mode and antagonistic property of this compound that differs considerably from HMA (5-(N,N-hexamethylene)amiloride), a well-characterized NAM of A(2A)AR. Taken together, our work would facilitate fragment-based screening of allosteric modulators, as well as guide the design of novel NAMs acting at the sodium ion pocket of class A GPCRs.
WOS关键词AMILORIDE ANALOGS ; BINDING ; LIGANDS ; DISCOVERY ; GPCRS ; AGONIST ; ASSAYS
资助项目Shanghai Municipal Government ; National Program on Key Basic Research Project of China[2018YFA0507004] ; National Program on Key Basic Research Project of China[2018YFA0507000] ; National Natural Science Foundation of China[31971362] ; National Natural Science Foundation of China[21704064] ; National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Science & Technology Major Project of China -Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science & Technology Major Project of China -Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; Fudan University ; ShanghaiTech University
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000664331200005
源URL[http://119.78.100.183/handle/2S10ELR8/296977]  
专题中国科学院上海药物研究所
通讯作者Wang, Ming-Wei; Zhou, Qingtong; Shui, Wenqing
作者单位1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
2.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
7.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Yan,Liu, Hongyue,Yang, Dehua,et al. Affinity Mass Spectrometry-Based Fragment Screening Identified a New Negative Allosteric Modulator of the Adenosine A(2A) Receptor Targeting the Sodium Ion Pocket[J]. ACS CHEMICAL BIOLOGY,2021,16(6):991-1002.
APA Lu, Yan.,Liu, Hongyue.,Yang, Dehua.,Zhong, Li.,Xin, Ye.,...&Shui, Wenqing.(2021).Affinity Mass Spectrometry-Based Fragment Screening Identified a New Negative Allosteric Modulator of the Adenosine A(2A) Receptor Targeting the Sodium Ion Pocket.ACS CHEMICAL BIOLOGY,16(6),991-1002.
MLA Lu, Yan,et al."Affinity Mass Spectrometry-Based Fragment Screening Identified a New Negative Allosteric Modulator of the Adenosine A(2A) Receptor Targeting the Sodium Ion Pocket".ACS CHEMICAL BIOLOGY 16.6(2021):991-1002.

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来源：上海药物研究所

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