期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 2, 页码 235-242出版社
NATURE PORTFOLIO
DOI: 10.1038/NCHEMBIO.2266
关键词
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资金
- Endeavour Research Fellowship from the Australian Government
- NHMRC & NHF CJ Martin Fellowship
- NHMRC [573732, 1074386]
- Australian Postgraduate Awards
- NHMRC Early Career Fellowship [1090408]
- NIH [R01 GM071872]
- [R0 AI118985]
- [R01 GM117424]
- [R21 AI121918]
- [R21 AI122211]
- National Health and Medical Research Council of Australia [1090408] Funding Source: NHMRC
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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