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Lead Discovery for Targeting G Protein-coupled Receptors

Siehler Wagner, Sandra and Jacob, Sandra (2011) Lead Discovery for Targeting G Protein-coupled Receptors. European Pharmaceutical Review, 16 (5). pp. 45-51. ISSN 1360-8606


G protein-coupled receptors (GPCRs) control a plethora of key physiological functions in every cell of an organism. GPCRs are therefore involved in many diseases, since altered ligand or receptor levels, and genetic or epigenetic modifications can lead to GPCR dysfunction and hence a pathophysiological phenotype. About one third of currently marketed drugs target GPCRs. The human genome contains 720-800 predicted GPCRs, and about half of them respond to olfactory/sensory signals, whereas the others are known or predicted to be activated by endogenous ligands and many of these represent potential drug targets. 77% of these non-sensory GPCRs belong to the class A (rhodopsin-like) family, whereas 14% represent class B (secretin-like) GPCRs, <1% belong to the class C (metabotropic receptor-like) or the atypical frizzled-/smoothened receptor class, and the remaining 25% are orphan receptors [1,2].
All of these families share a common overall structure consisting of an extracellular amino-terminus, a seven helical transmembrane domain and an intracellular carboxy-terminus [3] (Fig. 1). The diverse class A family is generally activated by small molecules binding to a pocket in the transmembrane domain (TMD), while in class B the natural ligands are peptides which use the TMD pocket and the large N-terminal domain, and in family C the ligands bind to the N-terminal domain alone, causing conformational changes that trigger receptor signalling.
Drug binding sites can be located in the TMD, in the extracellular or intracellular loop regions, in larger extracellular domains, and may be orthosteric or allosteric with respect to the natural ligand binding sites [4,5]. Pharmaceutical lead identification and optimization for GPCR drugs is completely dependent on cell-based assay systems (including cell membrane assays) because of limitations to obtain sufficient amounts of functional and stable protein for biochemical and biophysical assay methods. Such methods, however, are required to demonstrate on-target effects and to characterize the mechanism of action of compounds (or therapeutic antibodies) in an early lead discovery phase (Fig. 2).
Significant progress has been made in recent years in the development of membrane mimetics for receptor stabilization, of biochemical and biophysical methods, and of methods to enable X-ray structural studies for GPCRs. This review gives an update and thoughts on how these new developments may revolutionize the classical cellular lead discovery of GPCRs in the future.

Item Type: Article
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Keywords: GPCR, screening, structural biology
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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