Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug–Target Interactions

Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more ‘physiological’ regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.

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Guidelines for the Synthesis of Small-Molecule Irreversible Probes Targeting G Protein-Coupled Receptors

ChemMedChem ◽

10.1002/cmdc.201600066 ◽

2016 ◽

Vol 11 (14) ◽

pp. 1488-1498 ◽

Cited By ~ 8

Author(s):

Manuela Jörg ◽

Peter J. Scammells

Keyword(s):

G Protein ◽

Small Molecule ◽

G Protein Coupled Receptors ◽

G Protein Coupled

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Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.114.221606 ◽

2015 ◽

Vol 353 (2) ◽

pp. 246-260 ◽

Cited By ~ 81

Author(s):

Emma T. van der Westhuizen ◽

Celine Valant ◽

Patrick M. Sexton ◽

Arthur Christopoulos

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Allosteric Modulators ◽

G Protein Coupled

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The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis

Blood ◽

10.1182/blood-2008-08-174318 ◽

2009 ◽

Vol 113 (20) ◽

pp. 4942-4954 ◽

Cited By ~ 84

Author(s):

Yotis A. Senis ◽

Michael G. Tomlinson ◽

Stuart Ellison ◽

Alexandra Mazharian ◽

Jenson Lim ◽

...

Keyword(s):

G Protein ◽

Platelet Activation ◽

Drug Target ◽

Tyrosine Phosphatase ◽

Underlying Mechanism ◽

G Protein Coupled Receptors ◽

Bleeding Tendency ◽

Platelet Surface ◽

Surface Receptors ◽

G Protein Coupled

Abstract Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase–linked and G protein–coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein–coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug target.

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