HCAR3 / ImmunoACT - LARVOL DELTA

Gut microbiota-derived metabolites target C5AR1/KDM2A/HCAR3 axis in inflammatory bowel disease: a multi-machine learning algorithms and molecular docking study. (PubMed, Front Cell Infect Microbiol) - "Molecular docking confirmed stable binding of C5AR1 with 1,3-Diphenylpropan-2-Ol (-7.87 ± 0.83 kcal·mol-¹) and HCAR3 with 3-Indolepropionic Acid (-6.35 ± 0.70 kcal·mol-¹), both below -5.0 kcal·mol-¹. This study first constructs a "gut microbiota-metabolite-hub gene" axis in IBD, providing a computational framework for microbiota-targeted precision therapy, and identifying C5AR1/KDM2A/HCAR3 as computationally predicted diagnostic biomarkers and 1,3-Diphenylpropan-2-Ol/3-Indolepropionic Acid as candidate intervention molecules that warrant further experimental validation."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • IL17A

Evolutionary history and functional divergence of hydroxycarboxylic acid receptors in primates. (PubMed, Genome Biol Evol) - "Gene expression analyses further show that major divergence in tissue expression occurred early, following the duplication that generated HCAR1 and the HCAR2/3 lineage, while HCAR2 and HCAR3 retain largely overlapping expression profiles. Together, Our results suggest that HCAR3 receptors may have evolved repeatedly in apes, potentially contributing to refined lipid-sensing."

Journal • Metabolic Disorders • MAGEE1

A Machine Learning-Guided Approach for Identifying Potential HCAR1 Antagonists in Lactate-Driven Cancers. (PubMed, ACS Omega) - "An SVM model was trained on 144 ligands (66 agonists, 78 antagonists), listed in the IUPHAR/BPS Guide to Pharmacology, from 12 structurally related Class A GPCRs (HCAR1, HCAR2, HCAR3, OXER1, GPR35, SUCNR1, P2Y2, MCHR1, OPRD1, AGTR1, ADORA2A, and ADRA1A)...Based on ΔAffinity, off-target scores, and prediction confidence, Ketanserin, Cryptopyranmoscatone A1 diacetate, and Cefuroxime emerged as reference ligands with promising antagonistic potential, two of which are FDA-approved drugs...Overall, this work presents a proof-of-concept framework that integrates conformational docking, machine learning, and substructure interpretation to elucidate the chemical and structural determinants of HCAR1 antagonism. The findings provide fragment-level insights that may guide future bioisosteric and fragment-based design of selective antagonists for lactate-driven tumors."

Journal • Oncology • ADORA2A • MAGEE1 • SUCNR1

Structures of G-protein coupled receptor HCAR3 in complex with selective agonists reveal the basis for ligand recognition and selectivity. (PubMed, PLoS Biol) - "Moreover, combined with cAMP assay in HEK-293 cells, we have elucidated that the ligand selectivity between HCAR3 and HCAR2 depended on π-π interaction with F1073.32 (L1073.32 in HCAR2) and ligand-binding pocket size difference, facilitated by key residues difference V/L832.60, Y/N862.63, and S/W9123.48. Collectively, these structural insights lay the groundwork for developing HCAR3-specific drugs, potentially avoiding HCAR2-induced adverse effects."

Journal • Dyslipidemia • Metabolic Disorders