heterotrimeric G protein activity biosensors Marta Lopez-Balastegui, Antonella Di Pizio, Jiafei Mao, Jana Selent, et al. for their research on the Relevance of GPCR dynamics for receptor activation, signalling Principles of Pharmacology in Drug Discovery II - Advanced Methods for the Optimization of Candidate Selection

work on Highly biased agonism for GPCR ligands via nanobody tethering Elk Kossatz, Michel Bouvier, Jana Selent, et al. for their study on G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate pancreatic polypeptide from a structural, functional, and therapeutic perspective Structural basis for selectivity

Biased signaling frameworks centered on receptor conformations have a structural limitation when selectivity specificity to ligand-stabilized receptor conformations; this framework does not fully account for selectivity SBI-553 at NTSR1 functions as a PAM-agonist for arrestin while modulating G protein selectivity through This session with Kenneth Jacobson and Matteo Pavan examines the structural determinants that make selective the orthosteric pocket, with implications for PAM design across GPCRs How P2Y14 antagonists achieve selectivity

selectivity and signaling bias Quantifying Receptor Selectivity Requires Canceling the Cell In early True receptor selectivity must transcend the cell line. A “silent” ligand may be system-limited. No more “it looks selective.” Statistics decide. Receptor selectivity involves concentration separation.

This means they can be more selective, avoid pathway saturation, and preserve physiological nuance. that potentiate beneficial pathways without shutting down basal signaling entirely, or conversely, selectively The result is not just cleaner assay design but a sharper decision framework for selecting, prioritizing Translational Relevance: From Bench to Clinic Misjudging orthosteric vs allosteric behavior can derail dose selection

GPCR community live this week to examine what happens when GPCR selectivity is encoded not at the receptor GPCR Selectivity: Allosteric Modulators as Intracellular Molecular Glues Standard models attribute signaling specificity to ligand-stabilized receptor conformations — a framework that does not fully account for selectivity Binder2030 addresses this gap — a curated affinity selection-mass spectrometry dataset comprising 3,384 and molecular glues — and how these unconventional ligand classes address long-standing challenges in selectivity

In this article, you'll learn: Four reasons why bias measurements improve candidate selection at every Bias measurements are essential for accurate selectivity profiling. may show far less selectivity when β-arrestin signaling is included. Without multi-pathway assays, selectivity assessments can be misleading. A simple method for quantifying functional selectivity and agonist bias.

October 2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric opportunities to examine the dynamic fluxes in the 3D architecture of the receptors, as the basis of ligand selectivity Constituent structural motifs cooperatively transform ligand selectivity into specific functions, thus

therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective unique ligand-binding mode, involving an allosteric sub-pocket, which clarifies the receptor subtype selectivity

November 2022 "Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

October 2022 Discovery and In Vivo Evaluation of ACT-660602: A Potent and Selective Antagonist of the hit, we describe the iterative optimization of a chemical series culminating in the discovery of the selective

recently presented this important pre-clinical work at SIRS2022 confirming the ability of the highly selective

September 2022 Fly casting with ligand sliding and orientational selection supporting complex formation with an accompanying rapid reduction of the molecular orientational variety of bosentan (orientational selection

Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity

pharmacology, biology, behavior, and neurophysiology "The awareness of the potential importance of functional selectivity A major pan-receptor focus has been to identify GPCR-selective ligands that have bias in G protein-dependent

August 2022 GRK2 selectively attenuates the neutrophil NADPH-oxidase response triggered by β-arrestin

April 2022 Addex Expands Pipeline With Selective M4 Positive Allosteric Modulator Program For The Treatment Of Schizophrenia & Other Psychotic Disorders "New Series of Potent and Selective Compounds Identified pioneering allosteric modulation-based drug discovery and development, announced today that it has moved a selective

August 2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective The structural basis for G protein subtype selectivity by these GPCRs remains elusive. that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity

This phenomenon, biased signaling  (also called functional selectivity), means that two molecules targeting The therapeutic logic is sound: if signaling pathways are separable, they are potentially selectable. (positive or negative allosteric modulators, PAMs and NAMs), and crucially, can do so in a pathway-selective Functional Selectivity in Practice: Reading the Full Signaling Fingerprint Using complementary assay formats provides the needed mechanistic depth to define the functional selectivity  that may ultimately

May 2022 "We are thrilled to announce that our co-founder Margaux Duchamp has been selected as a 30 under

subset of this field with accelerating importance: transducer biosensors measuring receptor-coupling and selectivity

.- Jan Steyaert, scientific director of the VIB-VUB Center for Structural Biology, Vlaams Instituut Biotechnologie Jan Steyaert will be presented with the Gabbay Award at Brandeis University on October 27 when he will

Tirzepatide's success underscores the potential of designing drugs that selectively target beneficial By selectively targeting specific signaling pathways, it is possible to develop drugs with improved efficacy Zhang, H., et al., Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic JAMA Internal Medicine, 2024. 184 (9): p. 1056-1064. 11. https://www.evaluate.com/thought-leadership/

What if a seemingly “clean” antagonist profile reflects silent allosteric modulation? What if probe dependence is quietly signaling selective safety implications? Probe dependence reveals hidden selectivity and efficacy shifts It becomes critical in both screening becomes essential when: Distinguishing affinity-dominant from efficacy-dominant agonists Detecting silent Yet rare adverse effects may only emerge after large-scale exposure, and selectivity must still be demonstrated

This is the silent advantage of many successful drugs: they bind tightly or covalently , making target When irreversible mechanisms are designed, not discovered by accident , they become strategic levers: Selective Tunable kinetic selectivity. Dosing regimens aligned with biology, not just exposure. When they’re ignored, they become sources of silent failure : under-penetration, persistent off-target

. ✅ Why adjusting system sensitivity  can uncover hidden efficacy, silent antagonism, or even inverse in GPCR Research In GPCR pharmacology, the conversation often centers on ligand properties—affinity, selectivity By increasing sensitivity, so-called “silent” antagonists reveal themselves as weak agonists. What if your “silent antagonist” is actually a low-level agonist in disguise—and how will that matter

setting go/no-go points, and de-risking programs from hit validation through development candidate selection Read The Full Article GPCR Publication Highlights   Chemokine–GPCR Selectivity Unveiled Sequence- and structure-based analysis reveals how conserved and variable regions across chemokines and their receptors drive selectivity To start receiving our newsletter in your inbox every Thursday, follow these simple steps: Select the Select ' New to this site? Sign Up' Complete the registration form.

Plus, Celtarys explores ligand selection for better assays, and co-founder Dr. maturation CXCL13/CXCR5 emerges as a high-potential pain target ST171, a biased 5‑HT1A agonist, delivers selective Terry’s Corner gives you timeless and timely tools to improve selectivity, model efficacy, and design This novel agonist activates Gi/o selectively , avoiding β-arrestin and showing strong pain relief in

conformation—and why this can’t be ignored  ✅ Practical examples of how probe dependence  alters efficacy, selectivity minutes—to equilibrate  ✅ A framework for designing or troubleshooting allosteric modulators with built-in selectivity conformation , and how that physical truth underpins allosteric design, signal bias, and functional selectivity Design with Intelligence, Not Assumptions Whether you're aiming to discover PAMs, NAMs, or bias-selective the principles in this lecture equip you to design ligands that not only bind, but bind with purpose —selectively

enhances metabolic outcomes Ghrelin receptor flips D2 signaling without a ligand MOR-PAM shows G protein-selective It emphasizes scaffold selection, linker optimization, and assay compatibility to enhance target binding A MOR-positive allosteric modulator (BMS-986122) selectively enhances opioid signaling  through specific