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.
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This work was supported in part by an Endeavour Research Fellowship from the Australian Government to T.N., an NHMRC & NHF CJ Martin Fellowship (N.J.S.), NHMRC Program Grants 573732 and 1074386 (R.M.G.), and Australian Postgraduate Awards (T.N. & J.L.J.C.). A.G.S. is supported by NHMRC Early Career Fellowship 1090408. R.A., I.K. and A.V.I. are supported by the NIH Grant R01 GM071872. I.K. is supported by R01 AI118985, R01 GM117424, R21 AI121918 and R21 AI122211. N.J.S. thanks the Mostyn Family Foundation for philanthropic support.
The authors declare no competing financial interests.
Supplementary Results and Supplementary Figures 1–7. (PDF 4543 kb)
Pairwise comparison of GPCR–CoINPocket scores between Class A GPCRs. (XLSX 23959 kb)
List of class A G protein–coupled receptors entries in the Pocketome. (XLSX 26281 kb)
Raw pairwise contact strength profiled binding site similarities between class A GPCRs. (XLSX 10 kb)
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Ngo, T., Ilatovskiy, A., Stewart, A. et al. RETRACTED ARTICLE: Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat Chem Biol 13, 235–242 (2017). https://doi.org/10.1038/nchembio.2266
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