title: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors.
abstract: 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.
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Tony
authors.identifier: 0000-0002-6779-2546
authors.initials: T
authors.lastname: Ngo
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Ilatovskiy
authors.affiliation: St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.|Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Alastair G
authors.identifier: 0000-0002-2070-6030
authors.initials: AG
authors.lastname: Stewart
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: James L J
authors.initials: JL
authors.lastname: Coleman
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: McRobb
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: R Peter
authors.initials: RP
authors.lastname: Riek
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Robert M
authors.identifier: 0000-0002-1042-2587
authors.initials: RM
authors.lastname: Graham
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Irina
authors.identifier: 0000-0001-9083-7039
authors.initials: I
authors.lastname: Kufareva
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.|St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Smith
mesh_terms: D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled