Molecular Modeling of an Orphan GPR18 Receptor

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Author(s): Kamil J. Kuder , Tadeusz Karcz, Maria Kaleta, Katarzyna Kiec-Kononowicz*.

Journal Name: Letters in Drug Design & Discovery

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Background: One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. Methods: One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Therefore, the goal of this study was to build a GPR18 inactive form homology model on the basis of the evolutionary closest homologous template: Human P2y1 Receptor crystal structure. Results: Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

Keywords: GPR18, N-arachidonyl glycine receptor, GPCR, orphan receptors, cannabidiol

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(E-pub Ahead of Print)
DOI: 10.2174/1570180815666180810114847
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