Retraction Note: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors.

Abstract

The ‘CoINPocket’ approach identifies pharmacological similarities between G protein–coupled receptors. On the basis of predicted pharmacological similarity to a few phylogenetically unrelated receptors, the approach identified surrogate ligands for the orphan receptor GPR37L1. Understanding the pharmacological similarity of G protein–coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor–ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR–CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand–residue interactions observed in crystallographically characterized GPCRs. GPCR–CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR–CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families.