Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84
Laura Jenkins, Sara Marsango, Sarah J. Mancini, Zobaer Al Mahmud, Angus J. Morrison, Stuart P. McElroy, K.A. Bennett, Matt Barnes, Andrew B. Tobin, Irina G. Tikhonova, Graeme Milligan
Abstract
-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.