Issue 12, 2018

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

Abstract

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.

Graphical abstract: High-throughput identification of G protein-coupled receptor modulators through affinity mass spectrometry screening

Supplementary files

Article information

Article type
Edge Article
Submitted
31 okt 2017
Accepted
19 feb 2018
First published
20 feb 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 3192-3199

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

S. Qin, M. Meng, D. Yang, W. Bai, Y. Lu, Y. Peng, G. Song, Y. Wu, Q. Zhou, S. Zhao, X. Huang, J. D. McCorvy, X. Cai, A. Dai, B. L. Roth, M. A. Hanson, Z. Liu, M. Wang, R. C. Stevens and W. Shui, Chem. Sci., 2018, 9, 3192 DOI: 10.1039/C7SC04698G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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