Ngo, Tony and Ilatovskiy, Andrey V and Stewart, Alastair G and Coleman, James L J and McRobb, Fiona M and Riek, R Peter and Graham, Robert M and Abagyan, Ruben and Kufareva, Irina and Smith, Nicola J (2017) Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nature Chemical Biology, 13 (2). pp.235-242. ISSN 1552-4469 (PMC OA)
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Additional Information: | This article is available for free from the PMC website: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247308/ |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 23 Jan 2017 03:22 |
| Last Modified: | 11 Jan 2019 03:17 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/534 |
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