Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84.
Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84.
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DOI：
10.1021/acsptsci.1c00151
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发表时间：
2021-10-08
影响因子：
--
通讯作者：
Milligan G
中科院分区：
文献类型：
--
作者：
Jenkins L;Marsango S;Mancini S;Mahmud ZA;Morrison A;McElroy SP;Bennett KA;Barnes M;Tobin AB;Tikhonova IG;Milligan G
GPR 84是一种表征不佳的、名义上孤儿的促炎性G蛋白偶联受体，其可以被中链长度脂肪酸激活。作为炎症性肠病和特发性肺纤维化的拮抗剂配体的潜在治疗靶点，它吸引了相当大的兴趣。从一个小分子库中成功筛选了超过30万种化合物，然后对大约50种药物样命中物进行了详细分析，确定3-（（5，6-双（4-甲氧基苯基）-1，2，4-三嗪-3-基）甲基）-1H-吲哚为人GPR 84的高亲和力和高选择性竞争性拮抗剂。核结构的二碘化形式的氚化产生[3 H]3-（（5，6-二苯基-1，2，4-三嗪-3-基）甲基）-1H-吲哚，其允许有效测量转染细胞系和脂多糖处理的THP-1单核细胞/巨噬细胞中的受体水平。尽管该化合物系列在小鼠GPR 84处缺乏显著的亲和力，但同源性建模和分子动力学模拟为该差异提供了潜在的基本原理，并且将小鼠GPR 84中的两个残基改变为人类直向同源物中的等同氨基酸，预测打开拮抗剂结合口袋，验证了该模型。其他物种直向同源物的序列比对进一步预测了化合物作为高亲和力拮抗剂在猕猴、猪和狗GPR 84处的结合，但在大鼠直向同源物处不结合，并且药理学实验证实了这些预测。这些研究提供了一类新的GPR 84拮抗剂，其显示通过受体建模和诱变定义的物种选择性。
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.
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影响因子：
3.5
作者：
Nagasaki, Hiroshi;Kondo, Takaaki;Hamada, Yoji
通讯作者：
Hamada, Yoji
影响因子：
--
作者：
Quon T;Lin LC;Ganguly A;Tobin AB;Milligan G
通讯作者：
Milligan G
影响因子：
7.3
作者：
通讯作者：
--
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
激动剂和拮抗剂对 G 蛋白偶联受体 84 (GPR84) 的调节
影响因子：
7.3
作者：
Chen, Lin-Hai;Zhang, Qing;Nan, Fa-Jun
通讯作者：
Nan, Fa-Jun