A Pharmacological Organization of G Protein-coupled Receptors

Protein classification typically uses structural, sequence, or functional similarity. Here we introduce an orthogonal method that organizes proteins by ligand similarity, focusing here on the class A G protein-coupled receptor (GPCR) protein family. Comparing a ligand-based dendogram to a sequence-based one, we sought examples of GPCRs that were distantly linked by sequence but neighbors by ligand similarity. Experimental testing of compounds predicted to link three of these new pairs confirmed the predicted association, with potencies ranging from the low-nanomolar to low-micromolar. We then identified hundreds of non-GPCRs closely related to GPCRs by ligand similarity, including the CXCR2 chemokine receptor to Casein kinase I, the cannabinoid receptors to epoxide hydrolase 2, and the α(2) adrenergic receptor to phospholipase D. These, too, were confirmed experimentally. Ligand similarities among these targets may reflect a chemical integration in the time domain of molecular signaling.