Undisclosed GPCR modulators / Boehringer Ingelheim, Evotec - LARVOL DELTA

Integration of GPCR Modeling with QM for Drug Design: Academic and Industry Collaboration. (PubMed, Methods Mol Biol) - "The methodologies developed through this partnership have been successfully deployed across multiple GPCR discovery programs and now form part of the broader computational chemistry toolkit used in both academia and industry. This collaboration also stands as a model of how long-term partnerships between academia and the pharmaceutical industry can accelerate scientific innovation and deliver practical technologies for drug discovery."

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A high throughput screening platform for label-free identification and characterization of GPCR ligands using impedance-based real-time cellular analysis. (PubMed, SLAS Discov) - "Our study presents the integration of the xCELLigence RTCA HT system into a fully automated HTS systems, to enable large-scale screening for GPCR agonists. The results obtained in a "proof-of-concept" pilot HTS demonstrate the compatibility of impedance-based RTCA with robotic HTS platforms, as well as the potential of this method for the identification of GPCR ligands."

Journal

Thermodynamic Profiling and Fragment Screening of GPCRs Using Grating-Coupled Interferometry. (PubMed, SLAS Discov) - "Nano differential scanning fluorimetry (nanoDSF) was subsequently applied to confirm binding for the identified hits. Collectively, this study establishes GCI-based analysis as a powerful and information-rich platform for kinetic, thermodynamic, and fragment-based discovery on GPCR targets, which is particularly valuable for early-stage drug discovery."

Journal • ADORA2A

A novel fusion tool to enable G protein-coupled receptor structure determination. (PubMed, Acta Crystallogr D Struct Biol) - "Focused refinement of the A2AR region improved the local resolution and map detail in the orthosteric site, thereby allowing confident modelling of the antagonist ligand, ZM241385, which matches previously described X-ray crystallographic structures. This new fusion provides an alternative option for GPCR structure determination, with several potential benefits compared with existing tools, such as a more favourable position relative to the GPCR to reduce potential clashes."

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Serotonin signaling modulates growth and motility in juvenile Fasciola hepatica. (PubMed, PLoS Negl Trop Dis) - "In silico analyses confirmed all F. hepatica life stages express a complete 5-HT signaling pathway encompassing genes encoding proteins for 5-HT synthesis, transport, and reuptake, as well as five putative 5-HT G protein-coupled receptors (GPCRs)...Notably, sustained 5-HT exposure promoted juvenile growth, but these effects were not blunted by receptor-RNAi. The findings emphasize a central role of serotonin signaling in both juvenile motility and growth, exposing novel aspects of receptor function and encouraging therapeutic exploitation for liver fluke control."

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Deep learning-aided inter-species-comparison reveals shared and distinct molecular patterns in cynomolgus monkey and humans following non-specific T cell activation. (PubMed, Front Immunol) - "Specific transcriptional clusters related to metabolic reprogramming emerged in CD8+ T cells and related to inflammatory and antiviral programs in NK cells at 24 hours post-stimulation in both species, with stronger regulation of pathways related to cell cycle progression, DNA replication, and GPCR signaling in the emerging CD8+ T cell cluster in monkeys than in humans...Across time, we observed a consistent decline in the expression of receptors and ligands involved in cell-cell communication in most cell types, however, the initial levels were higher in humans and the decline more pronounced. Our proposed computational framework enables systematic cross-species time series analyses, advancing translational research and contributing to improved development of immunomodulating therapies."

Clinical • Journal • Preclinical • ACACA • CD14 • CD8

Nerandomilast Paves the Way for Novel Strategies in IPF Drug Discovery (ATS 2025) - "These effects were linked to activated cAMP-associated pathways, G-protein-coupled receptor (GPCR) signaling events, mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta 1(TGFβ1) signaling. Nerandomilast's efficacy in IPF may be attributable to effects on an array of patho-mechanisms in epithelial, endothelial, and immune cells, in addition to fibroblasts. Cutting edge technologies can build on such principles to transform drug discovery strategies. Next generation targets will influence our newly characterized pathologic niches, with the bold aim to not only limit disease but return functionality to the lung."

Late-breaking abstract • Acute Lung Injury • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease

Downstream Signaling of Muscarinic M4 Receptors Is Regulated by Receptor Density and Cellular Environment. (PubMed, Pharmacol Res Perspect) - "This study provides a side-by-side comparison of the activity of structurally diverse M4 agonists and highlights compound-specific activation of GPCR intracellular signaling pathways. The data offer new insights into M4 receptor pharmacology that may aid in the development of novel therapies for the treatment of psychiatric diseases."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Insights Into the Cellular and Molecular Mechanisms Behind the Antifibrotic Effects of Nerandomilast. (PubMed, Am J Respir Cell Mol Biol) - "Treatment with nerandomilast significantly activated cAMP-associated pathways and G-protein-coupled receptor (GPCR) signaling events while inhibiting mitogen-activated protein kinase (MAPK) signaling pathways and transforming growth factor beta (TGFβ) signaling. These findings highlight nerandomilast's potential therapeutic use in IPF by providing insights into its cellular and molecular actions. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)."

Journal • Acute Lung Injury • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • VCAM1

Structural basis for lipid-mediated activation of G protein-coupled receptor GPR55. (PubMed, Nat Commun) - "GPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, and metabolic diseases...The structural observations are supported by mutagenesis and functional experiments employing G protein dissociation assays. These findings will be of importance for the structure-based development of drugs targeting GPR55."

Journal • Metabolic Disorders • Oncology • GPR55

A non-canonical mechanism of GPCR activation. (PubMed, Nat Commun) - "We validate the predictions of our atomic-level simulations by targeted mutagenesis; specific mutations that disrupt interactions with the intracellular loop convert these agonists into inverse agonists. Further analysis suggests that allosteric ligands could regulate the signaling of many other GPCRs via a similar mechanism, offering rich possibilities for precise control of pharmaceutically important targets."

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Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs. (PubMed, Biochem Pharmacol) - "In contrast neutral or weak negative/positive allosteric modulation was observed with peptides assessed at the GCGR and CTR. This study expands our knowledge on class B1 GPCR allosteric modulation and may have implications for future structural and drug discovery efforts targeting the class B1 GPCR subfamily."

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A bistable inhibitory optoGPCR for multiplexed optogenetic control of neural circuits. (PubMed, Nat Methods) - "PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping."

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Cooperativity by Low Extracellular pH and Tumor Necrosis Factor α (TNFα) in Ovarian Cancer GPCR1 (OGR1)-dependent Cytokine Production in Airway Smooth Muscle (ATS 2024) - "0 with the (balanced Gq- and Gs- activating) OGR1 agonist lorazepam modestly increased IL-6 which was further enhanced by TNFα and decreased media pH. Low extracellular pH and TNFα increase IL-6 in a cooperative manner, dependent on OGR1 and its Gq-coupled signaling. Targeting OGR1 with small molecule antagonists or Gs-biased agonists has potential anti-inflammatory utility."

Asthma • Immunology • Oncology • Ovarian Cancer • Pulmonary Disease • Respiratory Diseases • Solid Tumor • IL6 • PTGS2 • TNFA

Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68. (PubMed, Comput Struct Biotechnol J) - "Proton-sensing G Protein Coupled Receptors (GPCRs) sense changes in the extracellular pH to effect cell signaling for cellular homeostasis...We found that GPR68 hosts an extended hydrogen-bond network that inter-connects the extracellular histidine cluster to the internal carboxylic triad, and which can even reach groups at the cytoplasmic G-protein binding site. Taken together, results suggest that GPR68 relies on dynamic, hydrogen-bond networks to inter-connect extracellular and internal proton-binding sites, and to elicit conformational changes at the cytoplasmic G-protein binding site."

Journal • Oncology • Solid Tumor

Control of sustained attention and impulsivity by G-protein signalling in parvalbumin interneurons of the anterior cingulate cortex. (PubMed, Transl Psychiatry) - "These effects largely resembled those of the ADHD medication atomoxetine. In contrast, if hM3Dq was activated in Sst-interneurons, no improvement of impulse control was observed, and a reduction of incorrect responses was only induced at high agonist levels and accompanied by reduced motivational drive. These results suggest that the activation of GPCRs expressed specifically in PV-cells of the ACC may be a viable strategy to improve certain aspects of sustained attention, impulsivity and hyperactivity in ADHD."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Discovery and in vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human PAC Receptor. (PubMed, Mol Pharmacol) - "The human pituitary adenylate cyclase activating polypeptide receptor (hPAC-R), a class B GPCR identified almost 30 years ago, represents an important pharmacological target in the areas of neuroscience, oncology, and immunology...We identified and thoroughly characterized a novel, potent and selective SMOL antagonist of hPAC-R (acting in an allosteric manner). These characteristics make BAY 2686013 an ideal tool for further studies."

Journal • Preclinical • Oncology • Pain • ADCYAP1

Ligand recognition and activation of neuromedin U receptor 2. (PubMed, Nat Commun) - "Combined with functional and computational data, the structure reveals the key factors that govern the recognition and selectivity of peptide agonist as well as non-peptide antagonist, providing the structural basis for design of novel and highly selective drugs targeting NMU2. In addition, a 25-degree rotation of G protein in reference to NMU2 is also observed compared in other structures of class A GPCR-G complexes, suggesting heterogeneity in the processes of G protein-coupled receptors (GPCRs) activation and G protein coupling."

Journal • Genetic Disorders • Obesity • NMU

Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2. (PubMed, Elife) - "Activation of G protein-coupled receptors (GPCRs) is an allosteric process...Moreover, we found that the effect of allosteric modulators on the receptor dynamics is complex and depend on the orthosteric ligand. Collectively, our findings provide a structural mechanism of allosteric modulation in mGluR2 and suggest possible strategies for design of future modulators."

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"Good news for #kinin #GPCR researchers. Thanks @Boehringer for #opnMe initiative." (,@Jiafei_Mao)

"Abstract deadline is TODAY!! What are you waiting for? #ernest6 #GPCRsig #signallingmap @DrGPCR @Boehringer @zenbrainest @IctacVancouver @ACSPublications @ACSBioMed @aisb_0 @karantarina @miriamscarpa4 @bermudez_lab https://t.co/TfaTQLJ4ix" (,@ErnestNetwork)

"@IctacVancouver @DrGPCR @ACSPublications @ACSBioMed @Boehringer @karantarina @aisb_0" (,@ErnestNetwork)

"InterAx and @Boehringer take first steps towards collaborating to unlock orphan targets leveraging InterAx AI driven discovery platform. Collaborative efforts aim to accelerate and improve the prediction of first in class small molecule agonists for a challenging orphan GPCR 💊" (,@InterAxBiotech)

GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1. (PubMed, Nat Commun) - "We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism."

Journal • SMAD3

Predicting Residence Time of GPCR Ligands with Machine Learning. (PubMed, Methods Mol Biol) - "Finally, two different workflows for predicting residence time with machine learning are outlined. The first is a single-target model trained on ligand features; the second is a multi-target model trained on features generated from molecular dynamics simulations."

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