Identifying ligands at orphan GPCRs: current status using structure-based approaches

British Journal of Pharmacology
Tony NgoNicola J Smith

Abstract

GPCRs are the most successful pharmaceutical targets in history. Nevertheless, the pharmacology of many GPCRs remains inaccessible as their endogenous or exogenous modulators have not been discovered. Tools that explore the physiological functions and pharmacological potential of these 'orphan' GPCRs, whether they are endogenous and/or surrogate ligands, are therefore of paramount importance. Rates of receptor deorphanization determined by traditional reverse pharmacology methods have slowed, indicating a need for the development of more sophisticated and efficient ligand screening approaches. Here, we discuss the use of structure-based ligand discovery approaches to identify small molecule modulators for exploring the function of orphan GPCRs. These studies have been buoyed by the growing number of GPCR crystal structures solved in the past decade, providing a broad range of template structures for homology modelling of orphans. This review discusses the methods used to establish the appropriate signalling assays to test orphan receptor activity and provides current examples of structure-based methods used to identify ligands of orphan GPCRs. Linked Articles This article is part of a themed section on Molecular Pharmacology of...Continue Reading

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Citations

Sep 30, 2016·British Journal of Pharmacology·R J Summers
Mar 14, 2017·Nature Chemical Biology·Katherine LansuBryan L Roth
Dec 20, 2016·Nature Chemical Biology·Tony NgoNicola J Smith
Jul 15, 2017·British Journal of Pharmacology·Erika CeconRalf Jockers
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Aug 28, 2021·Chemical Reviews·Jack L BennettWilliam A Donald

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