Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical & Medicinal Chemistry, University of Bonn, 53121 Bonn, Germany

Research Training Group 1873, University of Bonn, 53127 Bonn, Germany

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland

Author to whom correspondence should be addressed.

Biomolecules 2020, 10(5), 686; https://doi.org/10.3390/biom10050686

Received: 10 March 2020 / Revised: 22 April 2020 / Accepted: 23 April 2020 / Published: 29 April 2020

(This article belongs to the Collection In Silico Drug Design for GPCRs: Big Data for Small Molecule Discovery)

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Abstract

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆⁹-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target. View Full-Text

Keywords: cannabinoid; docking studies; GPCR; GPR18; MD simulation; orphan GPCRs

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MDPI and ACS Style

Neumann, A.; Engel, V.; Mahardhika, A.B.; Schoeder, C.T.; Namasivayam, V.; Kieć-Kononowicz, K.; Müller, C.E. Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18. Biomolecules 2020, 10, 686. https://doi.org/10.3390/biom10050686

AMA Style

Neumann A, Engel V, Mahardhika AB, Schoeder CT, Namasivayam V, Kieć-Kononowicz K, Müller CE. Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18. Biomolecules. 2020; 10(5):686. https://doi.org/10.3390/biom10050686

Chicago/Turabian Style

Neumann, Alexander, Viktor Engel, Andhika B. Mahardhika, Clara T. Schoeder, Vigneshwaran Namasivayam, Katarzyna Kieć-Kononowicz, and Christa E. Müller. 2020. "Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18" Biomolecules 10, no. 5: 686. https://doi.org/10.3390/biom10050686

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Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

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