Milligan, G. et al. (2021) Discovery and characterization of novel antagonists of the proinflammatory orphan receptor GPR84. ACS Pharmacology and Translational Science, 4(5), pp. 1598-1613. (doi: 10.1021/acsptsci.1c00151) (PMID:34661077) (PMCID:PMC8506611)
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Abstract
GPR84 is a poorly characterized, nominally orphan, proinflammatory G protein-coupled receptor that can be activated by medium chain length fatty acids. It is attracting considerable interest as a potential therapeutic target for antagonist ligands in both inflammatory bowel diseases and idiopathic pulmonary fibrosis. Successful screening of more than 300 000 compounds from a small molecule library followed by detailed analysis of some 50 drug-like hits identified 3-((5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl)methyl)-1H-indole as a high affinity and highly selective competitive antagonist of human GPR84. Tritiation of a di-iodinated form of the core structure produced [3H]3-((5,6-diphenyl-1,2,4-triazin-3-yl)methyl)-1H-indole, which allowed effective measurement of receptor levels in both transfected cell lines and lipopolysaccharide-treated THP-1 monocyte/macrophage cells. Although this compound series lacks significant affinity at mouse GPR84, homology modeling and molecular dynamics simulations provided a potential rationale for this difference, and alteration of two residues in mouse GPR84 to the equivalent amino acids in the human orthologue, predicted to open the antagonist binding pocket, validated this model. Sequence alignment of other species orthologues further predicted binding of the compounds as high affinity antagonists at macaque, pig, and dog GPR84 but not at the rat orthologue, and pharmacological experiments confirmed these predictions. These studies provide a new class of GPR84 antagonists that display species selectivity defined via receptor modeling and mutagenesis.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was funded by each of the Biotechnology and Biosciences Research Council (grant reference BB/T000562/ 1) to G.M. and A.B.T., and grant reference BB/R007101/1 to I.G.T., an ORBIT (Opportunities in Receptor Biology for Industrial Translation) grant from Sosei-Heptares to G.M. and A.B.T., the Medical Research Council (Confidence in Concept, grant number MC_PC_17160 (to G.M.)). Initial studies leading to these results was performed within the European Lead Factory (Programme ELFSC03_03) (to G.M.) and received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115489, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. Data for activity of compound 140 at species orthologues other than human and mouse was provided by Dr. Katrin Nowak-Reppel, Bayer AG Berlin, Germany. This project made use of computational time on Kelvin-2 (grant no. EP/T022175/1) G.M., A.B.T., and I.G.T. participate in the European COST Action CA18133 (ERNEST). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Jenkins, Mrs Laura and Tobin, Andrew and Mahmud, Zobaer Al and Mancini, Dr Sarah and Milligan, Professor Graeme and Marsango, Dr Sara |
| Authors: | Milligan, G., Jenkins, L., Marsango, S., Mancini, S., Mahmud, Z. A., Morrison, A., McElroy, S., Bennett, K., Barnes, M., Tobin, A., and Tikhonova, I. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | ACS Pharmacology and Translational Science |
| Publisher: | American Chemical Society |
| ISSN: | 2575-9108 |
| ISSN (Online): | 2575-9108 |
| Published Online: | 07 September 2021 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in ACS Pharmacology and Translational Science 4(5):1598-1613 |
| Publisher Policy: | Reproduced under a Creative Commons Licence |
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