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August 2022 "The atypical chemokine receptor 1 (ACKR1) was discovered on erythrocytes as the Duffy blood group antigen ( Cutbush et al., 1950 ), also called Duffy-antigen/receptor for chemokines, or DARC (

August 2022 "GPCRs in Medicinal Chemistry Event 8th RSC / SCI symposium on GPCRs in Medicinal Chemistry

But what if the real opportunity lies in the chemical matter we throw at them? Terry’s Corner: Why Chemistry Still Rules For decades, discovery focused on targets. But drugs aren’t just biology—they’re chemical matter. Terry Kenakin reveals how drug chemistry defines function, not just fit. . • Cheminformatics to Biologics : GPCR-focused chemical design is evolving—fast.

His lab sits at the crossroads of structure-based modeling, computational chemistry, and drug discovery Vast chemical libraries—sometimes billions of molecules—are sifted computationally to highlight potential That medicinal chemistry capacity is unusual for a modeling lab and provides a critical bridge between Notably, this isn’t contract computational chemistry—it’s strategic guidance  on target selection, ligand

the cost of one conference = a year of expert training — Premium Members Enjoy Over 50% Discount at Checkout

Starting from vercirnon, an intracellular C-C chemokine receptor type 9 (CCR9) antagonist and previous phase III clinical candidate for the treatment of Crohn's disease, we developed a chemical biology toolbox To chemically induce CCR9 degradation, we then developed the first PROTAC targeting the IABS of GPCRs

Latrophilin-1 drives neuron morphogenesis and shapes chemo- and mechanosensation-dependent behavior in

Chemical communication controls a wide range of behaviors via conserved signaling networks. In this study, we investigated the role of chemical signaling in axon regeneration in Caenorhabditis We demonstrate that the chemoreceptor genes, srg-36 and srg-37, which encode G protein-coupled receptors secretes a family of small-molecule pheromones called ascarosides, which serve various functions in chemical

August 2022 "Abstract Sigma receptor is a transmembrane non-GPCR protein expressed mainly in the endoplasmic reticulum membrane associated with mitochondria. It is classified into two types: Sigma-1 (S1R) and Sigma-2 (S2R) based on their biological functions. S1R has been implicated in many neurological disorders such as anxiety, schizophrenia, and depression. Therefore, S1R ligands possess a variety of potential clinical applications with a great interest in the treatment of neuropathic pain. In this study, we report the discovery of a novel lead compound for S1R binding, based on the thiazolidine-2,4-dione nucleus. We have explored hydrophobic groups of different sizes on both sides of the five-membered ring scaffold guided by the crystal structure of S1R. Six compounds showed more than 50% displacement of the radioligand at 10 µM concentration with compound 6c resulting in 100% displacement and a Ki of 95.5 nM. Moreover, compounds 6c and 6e showed a significant selectivity over S2R. In addition, molecular docking predicted that all the compounds showed the critical salt bridge with Glu172 with variable degrees of π-stacking interaction with Tyr103. Upon optimization, this series of compounds could represent potential clinically useful S1R ligands for pain management." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "CXCR1 and CXCR2 chemokine receptors, mainly activated by interleukin 8 (IL-8 or CXCL8), focus is currently being directed towards CXCR1/2 inhibitors, as these receptors primarily induce the chemotaxis

genes are transmembrane proteins and cytokines, such as viral G protein-coupled receptors (vGPCRs), chemokines , and chemokine-binding proteins.

August 2022 "CXCR1 and CXCR2 chemokine receptors, mainly activated by interleukin 8 (IL-8 or CXCL8), focus is currently being directed towards CXCR1/2 inhibitors, as these receptors primarily induce the chemotaxis

August 2022 "Chemokines, a subgroup of cytokines along with their receptors, are involved in various C-X-C motif chemokine receptor 4 (CXCR4), a G-protein-coupled receptor (GPCR), has one identified natural CXCR4 initiates several intracellular signaling pathways, regulating cell proliferation, survival, chemotaxis

Here, we investigated this issue in living cells for the CC chemokine receptor 5 (CCR5), a major receptor

Different strategies, such as antibodies, small chemicals, hormones, cytokines, and, recently, gene editing

Characterization of a new WHIM syndrome mutant reveals mechanistic differences in regulation of the chemokine gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine

One such platform is the chemogenetic DREADD (designer receptor exclusively activated by designer drugs

for Medicinal Products for Human Use (CHMP) "SAN CARLOS, Calif., Nov. 12, 2021 (GLOBE NEWSWIRE) -- ChemoCentryx

October 2022 "We describe production of the human A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor (GPCR) for 19F-NMR and single-molecule fluorescence (SMF) spectroscopy. We explain in detail steps shared between the two sample preparation strategies, including expression and isolation of A2AAR and assembly of A2AAR in lipid nanodiscs and procedures for incorporation of either 19F-NMR or fluorescence probes. Protocols for SMF experiments include sample setup, data acquisition, data processing, and error analysis. For complete details on the use and execution of this protocol, please refer to Wei et al. (2022) and Sušac et al. (2018)." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 "Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealised, therapeutic potential. Promising preclinical data supports the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopoeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such not optimal for clinical application due to unfavourable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties and a few such compounds have now undergone clinical trial. We review the current state of CB2 ligand development and progress in optimising physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 "Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealized, therapeutic potential. Promising preclinical data support the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such, not optimal for clinical application due to unfavorable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties and a few such compounds have now undergone clinical trials. We review the current state of CB2 ligand development and progress in optimizing physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds." Read more at the source #DrGPCR #GPCR #IndustryNews

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses - termed bias - potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct. Read full article

J Phys Chem B. 2016;120(11):2878-85. 36.         Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE, et al. Nature chemical biology. 2020;16(8):841-849. 44.         J Biol Chem. 2018;293(19):7466-7473. 45.         Teng X, Chen S, Wang Q, Chen Z, Wang X, Huang N, et al.

GPCR Podcast: Chemical Probes for GPCR Imaging with Dr. His work shows why chemical design can outperform antibodies and how rigorous assay validation bridges chemistry and biology effectively.

But behind the polite nods, your audience is checking out.

Kenakin  drew a sharp contrast between chemically reactive irreversible inhibitors and pseudo-irreversible Ranking Partial Agonists Without Losing Meaning Chemists want a single number. These GPCR pharmacology insights are essential for directing chemistry toward the property that actually

automated microscopy, multiplexed imaging, and computational analysis to evaluate cellular responses under chemical

Episode #177 The Experiment That Was Never Meant to Succeed When David Hodson’s lab teamed up with chemist Hodson: physiology, disease context, and imaging logic JB: chemistry, ligand engineering, mechanistic Collaboration, Chemistry, and the Pivot That Changed the Project Goal:  Develop a photo-switchable GPCR

Enter a long-term collaboration with chemist Dr.

Here, the Schild plot becomes a diagnostic tool  rather than a checkbox test: Slopes >1  often mean incomplete