Here we sought to further refine the comparisons of GPCR binding sites by analyzing both the persis- tence and the strength of residue–ligand interactions observed across the GPCR Pocketome—the set of annotated GPCR binding pockets that have been crystallographically characterized to date 16 . By enriching the binding-site comparisons with ligand contact strengths, a method we term GPCR–CoINPocket (GPCR contact- informed neighboring pocket), we organized and clustered all class A GPCRs into a hierarchical structure that closely reproduced pre- viously characterized pharmacological relationships.