Journal ArticleDOI
Emerging paradigms in GPCR allostery: implications for drug discovery
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TLDR
New findings have the potential to alter how screening for allosteric drugs is performed and may increase the chances of success in the development ofallosteric modulators as clinical lead compounds.Abstract:
Allosteric ligands bind to G protein-coupled receptors (GPCRs; also known as seven-transmembrane receptors) at sites that are distinct from the sites to which endogenous ligands bind. The existence of allosteric ligands has enriched the ways in which the functions of GPCRs can be manipulated for potential therapeutic benefit, yet the complexity of their actions provides both challenges and opportunities for drug screening and development. Converging avenues of research in areas such as biased signalling by allosteric ligands and the mechanisms by which allosteric ligands modulate the effects of diverse endogenous ligands have provided new insights into how interactions between allosteric ligands and GPCRs could be exploited for drug discovery. These new findings have the potential to alter how screening for allosteric drugs is performed and may increase the chances of success in the development of allosteric modulators as clinical lead compounds.read more
Citations
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Journal ArticleDOI
Trends in GPCR drug discovery: new agents, targets and indications
Alexander S. Hauser,Misty M. Attwood,Mathias Rask-Andersen,Helgi B. Schiöth,David E. Gloriam +4 more
TL;DR: An up-to-date analysis of all GPCR drugs and agents in clinical trials is reported, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs act at 108 unique GPCRs.
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Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.
TL;DR: It is hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 receptors through positive allosterics modulation ofCB1 receptors.
Journal ArticleDOI
The Current State of Peptide Drug Discovery: Back to the Future?
TL;DR: An emphasis is placed on describing research efforts to overcome the inherent weaknesses of peptide drugs, in particular their poor pharmacokinetic properties, and how these efforts have been critical to the discovery, design, and subsequent development of novel therapeutics.
Journal ArticleDOI
GPCR Dynamics: Structures in Motion
TL;DR: What is currently known about the flexibility and dynamics of GPCRs, as determined through crystallography, spectroscopy, and computer simulations is reviewed.
Journal ArticleDOI
Molecular control of δ-opioid receptor signalling
Gustavo Fenalti,Patrick M. Giguère,Vsevolod Katritch,Xi Ping Huang,Aaron Thompson,Vadim Cherezov,Bryan L. Roth,Raymond C. Stevens +7 more
TL;DR: The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as ‘efficacy switches’ at a prototypic G-protein-coupled receptor.
References
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Journal ArticleDOI
An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations
Noriko Makita,Junichiro Sato,Katsunori Manaka,Yuki Shoji,Atsuro Oishi,Makiko Hashimoto,Toshiro Fujita,Taroh Iiri +7 more
TL;DR: Observations indicate that a calcium-stimulated CaSR primed by a specific autoantibody adopts a unique conformation that activates Gq but not Gi, and speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.
Journal ArticleDOI
A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway *
Eugénie Goupil,Danaë Tassy,Carine B. Bourguet,Christiane Quiniou,Veronica Wisehart,Darlaine Pétrin,Christian Le Gouill,Dominic Devost,Hans H. Zingg,Michel Bouvier,Horacio Uri Saragovi,Sylvain Chemtob,Sylvain Chemtob,William D. Lubell,Audrey Claing,Terence E. Hébert,Stéphane A. Laporte +16 more
TL;DR: Findings regarding the allosteric and biased nature of PDC113.824 offer new mechanistic insights into FP receptor signaling relevant to parturition and suggest novel therapeutic opportunities for the development of new tocolytic drugs.
Journal ArticleDOI
Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2.
David J. Nicholls,Tomkinson Nicholas,Katherine Elisabeth Wiley,Anne Brammall,Lorna Bowers,Caroline Grahames,Alasdair Gaw,Premji Meghani,Philip Shelton,Tracey J. Wright,Philip Mallinder +10 more
TL;DR: It is concluded that residue 320 in CXCR2 forms part of a potential allosteric binding pocket on the intracellular side of the receptor, a site that is distal to the orthosteric site commonly assumed to be the location of antagonist binding to GPCRs.
Journal ArticleDOI
A novel multivalent ligand that bridges the allosteric and orthosteric binding sites of the M2 muscarinic receptor.
TL;DR: Data from two complementary kinetic studies assessing allosteric modulation of the receptor are consistent with the hypothesis that THRX-160209 binds in a multivalent manner to the M2 receptor, simultaneously occupying the orthosteric site and a spatially distinct allosterIC site.
Journal ArticleDOI
An intracellular allosteric site for a specific class of antagonists of the CC chemokine G protein-coupled receptors CCR4 and CCR5.
TL;DR: The existence of such a site that can be targeted for drug discovery has implications for screening assays for receptor antagonists, which would need to consider compound properties for access to this intracellular site.
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