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Chem Sci. 2018 Feb 20;9(12):3192-3199. doi: 10.1039/c7sc04698g. eCollection 2018 Mar 28.

High-throughput identification of G protein-coupled receptor modulators through affinity mass spectrometry screening.

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iHuman Institute , ShanghaiTech University , 201210 , Shanghai , China . Email:
College of Pharmacy , Nankai University , 300071 , Tianjin , China.
The National Center for Drug Screening , The CAS Key Laboratory of Receptor Research , Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 201203 , Shanghai , China . Email:
School of Life Science and Technology , ShanghaiTech University , 201202 , Shanghai , China.
Department of Pharmacology , Chapel Hill School of Medicine , University of North Carolina , NC 27599 Chapel Hill , USA.
GPCR Consortium , CA92078 San Marcos , USA.
School of Pharmacy , Fudan University , 201203 , Shanghai , China.


G protein-coupled receptors (GPCRs) represent the largest class of cell surface proteins and thus constitute an important family of therapeutic targets. Therefore, significant effort has been put towards the identification of novel ligands that can modulate the activity of a GPCR target with high efficacy and selectivity. However, due to limitations inherent to the most common techniques for GPCR ligand discovery, there is a pressing need for more efficient and effective ligand screening methods especially for the identification of potential allosteric modulators. Here we present a high-throughput, label-free and unbiased screening approach for the identification of small molecule ligands towards GPCR targets based on affinity mass spectrometry. This new approach features the usage of target-expressing cell membranes rather than purified proteins for ligand screening and allows the detection of both orthosteric and allosteric ligands targeting specific GPCRs. Screening a small compound library with this approach led to the rapid discovery of an antagonist for the 5-HT receptor and four positive allosteric modulators for GLP-1 receptor that were not previously reported.

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