Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139.

ABSTRACT: The orphan G protein-coupled receptor (GPCR) GPR139 attracts interest as a target for neuropsychiatric disorders. Whereas the physiological functions of GPR139 remain elusive, a high-resolution receptor structure is now available. To assess whether structural information enables ligand discovery, we computationally dock 235 million compounds to the GPR139 binding site. Of 68 top-ranked compounds evaluated experimentally, five are full agonists with potencies ranging from 160 nM to 3.6 µM. Structure-guided optimization identifies one of the most potent GPR139 agonists, and a cryo-EM structure of the receptor-ligand complex confirms the predicted binding mode. Functional characterization provides insights into GPR139 signalling, and one agonist elicits behavioural effects in mice. We also ex

SUBMITTER: Cabeza de Vaca I 

PROVIDER: S-EPMC12775434 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature