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
Discovery of potential negative allosteric modulators of mGluR5 from natural products using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies
TL;DR: This study presents a 3D quantitative pharmacophore model generated by using the HypoGen module in Discovery Studio 4.0 to discover potential mGluR5 negative allosteric modulators from natural products and analyzes the binding sites of these NAMs.
Journal ArticleDOI
Allosteric pathways in tetrahydrofolate sensing riboswitch with dynamics correlation network
TL;DR: A nucleotide/nucleotide dynamics correlation network based on an all-atom molecular dynamic simulation was used to reveal the regulation mechanism of a THF-sensing riboswitch and the underlying allosteric pathway provide fundamental insights for the regulation of THF sensing riboswitches.
Book ChapterDOI
The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance
TL;DR: The major role of ZnR/GPR39 is discussed as the link between extracellular Zn2+ and intracellular signaling pathways regulating the physiological function of epithelial and neuronal cells.
Journal ArticleDOI
Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs.
Barbara Pio,Harry R. Chobanian,Yan Guo,Josien Hubert B,William K. Hagmann,Michael W. Miller,Maria E. Trujillo,Melissa Kirkland,Daniel Kosinski,Joel Mane,Michele Pachanski,Boonlert Cheewatrakoolpong,Eric R. Ashley,Robert K. Orr,Michael Wright,Randal M. Bugianesi,Sarah Souza,Xiaoping Zhang,Jerry Di Salvo,Adam B. Weinglass,Richard Tschirret-Guth,Koppara Samuel,Qing Chen,Jackie Shang,James Lamca,Juliann Ehrhart,Ravi P. Nargund,Andrew D. Howard,Steven L. Colletti +28 more
TL;DR: Efforts were made to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites and to discover a novel G PR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR 40 receptor (AgoPAM).
Journal ArticleDOI
Allosteric modulation of GPCRs: From structural insights to in silico drug discovery.
TL;DR: In this paper , a systematic analysis of the currently available GPCR structures in complex with small-molecule allosteric ligands in terms of the location of allosterics pockets, receptor-ligand interactions, and the chemical features of the all-osteric modulators is presented.
References
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Journal ArticleDOI
International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels
William A. Catterall,K. G. Chandy,David E. Clapham,George A. Gutman,Franz Hofmann,Anthony J. Harmar,Darrell R. Abernethy,Michael Spedding +7 more
TL;DR: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined.
Journal ArticleDOI
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Krzysztof Palczewski,Takashi Kumasaka,Tetsuya Hori,Craig A. Behnke,H. Motoshima,Brian A. Fox,I. Le Trong,David C. Teller,Tetsuji Okada,Ronald E. Stenkamp,Masaki Yamamoto,Masashi Miyano +11 more
TL;DR: This article determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution and found that the highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the sevenhelix transmembrane motif.
Journal ArticleDOI
Crystal structure of the β2 adrenergic receptor-Gs protein complex.
Søren G. F. Rasmussen,Brian T. DeVree,Yaozhong Zou,Andrew C. Kruse,Ka Young Chung,Tong Sun Kobilka,Foon Sun Thian,Pil Seok Chae,Els Pardon,Els Pardon,Diane M. Calinski,Jesper Mosolff Mathiesen,Syed T. A. Shah,Joseph A. Lyons,Martin Caffrey,Samuel H. Gellman,Jan Steyaert,Jan Steyaert,Georgios Skiniotis,William I. Weis,Roger K. Sunahara,Brian K. Kobilka +21 more
TL;DR: This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR and the most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain.
Journal ArticleDOI
The Many Roles of Chemokines and Chemokine Receptors in Inflammation
TL;DR: The properties of chemokines and their receptors are discussed and the roles of these chemoattractants in selected clinical disorders are highlighted.
Journal ArticleDOI
Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.
Beili Wu,Ellen Y.T. Chien,Clifford D. Mol,Gustavo Fenalti,Wei Liu,Vsevolod Katritch,Ruben Abagyan,Alexei Brooun,Peter A. Wells,F. Christopher Bi,Damon J. Hamel,Peter Kuhn,Tracy M. Handel,Vadim Cherezov,Raymond C. Stevens +14 more
TL;DR: Five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling.
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