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A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts

文献类型：期刊论文

作者Zhang, Bingjie5; Zhao, Simeng5; Yang, Dehua2,3; Wu, Yiran5; Xin, Ye5; Cao, Haijie5; Huang, Xi-Ping4; Cai, Xiaoqing2,3; Sun, Wen2,3,6; Ye, Na7,8
刊名ACS CENTRAL SCIENCE
出版日期2020-02-26
卷号6期号:2页码:213-225
ISSN号2374-7943
DOI10.1021/acscentsci.9b01125
通讯作者Zhong, Guisheng() ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Shui, Wenqing(shuiwq@shanghaitec.edu.cn)
英文摘要Subtype selectivity and functional bias are vital in current drug discovery for G protein-coupled receptors (GPCRs) as selective and biased ligands are expected to yield drug leads with optimal on-target benefits and minimal side-effects. However, structure-based design and medicinal chemistry exploration remain challenging in part because of highly conserved binding pockets within subfamilies. Herein, we present an affinity mass spectrometry approach for screening herbal extracts to identify active ligands of a GPCR, the 5-HT2C receptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT2C without activating the 5-HT2A or 5-HT2B receptors. Remarkably, this novel ligand exhibited exclusive bias toward G protein signaling for which key residues were identified, and it showed comparable in vivo efficacy for food intake suppression and weight loss as the antiobesity drug, lorcaserin. Our study establishes an efficient approach to discovering novel GPCR ligands by exploring the largely untapped chemical space of natural products.
WOS关键词5-HT2C RECEPTOR ; MASS-SPECTROMETRY ; FUNCTIONAL SELECTIVITY ; CRYSTAL-STRUCTURE ; NATURAL-PRODUCTS ; OPIOID RECEPTOR ; DRUG DISCOVERY ; SEROTONIN ; LORCASERIN ; LIGANDS
资助项目National Key R&D Program of China[2018YFA0507000] ; National Key R&D Program of China[2018YFA0507004] ; National Key R&D Program of China[2016YFC0905900] ; National Key R&D Program of China[2017YFC1001300] ; National Mega R&D Program for Drug Discovery grants[2018ZX09711002-002-005] ; National Mega R&D Program for Drug Discovery grants[2018ZX09735-001] ; National Natural Science Foundation of China[31971362] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[31771130] ; Novo Nordisk-CAS Research Fund grant 2017 ; Novo Nordisk-CAS Research Fund grant 2019 ; ShanghaiTech University
WOS研究方向Chemistry
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000517832800016
源URL[http://119.78.100.183/handle/2S10ELR8/281260]  
专题中国科学院上海药物研究所
通讯作者Zhong, Guisheng; Wang, Ming-Wei; Shui, Wenqing
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Univ N Carolina, Dept Pharmacol, NIMH Psychoact Drug Screening Program, Sch Med, Chapel Hill, NC 27599 USA
5.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Soochow Univ, Jiangsu Key Lab Neuropsychiat Dis, Suzhou 215123, Peoples R China
8.Soochow Univ, Coll Pharmaceut Sci, Suzhou 215123, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Bingjie,Zhao, Simeng,Yang, Dehua,et al. A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts[J]. ACS CENTRAL SCIENCE,2020,6(2):213-225.
APA Zhang, Bingjie.,Zhao, Simeng.,Yang, Dehua.,Wu, Yiran.,Xin, Ye.,...&Shui, Wenqing.(2020).A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts.ACS CENTRAL SCIENCE,6(2),213-225.
MLA Zhang, Bingjie,et al."A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts".ACS CENTRAL SCIENCE 6.2(2020):213-225.

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来源：上海药物研究所

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