HCAR3 / ImmunoACT - LARVOL DELTA

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