Hot topics: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors.

Presenting 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.

[1] Ngo et al. (2017). Nat. Chem. Biol.  13(2):235-242. Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. [PMID: 27992882]

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