The nuclear receptor Nur77 is a transcription factor belonging to the NR4A subfamily. Upon activation, it regulates a wide array of biological and pathophysiological processes by modulating the expression of its target genes. Previous findings have classified Nur77 as an orphan receptor because of the discovery of a structurally atypical ligand-binding domain and the lack of identification of an endogenous ligand. Nevertheless, recent studies have uncovered several endogenous, natural, and small synthetic molecules that can bind to and activate Nur77. However, developing selective and potent Nur77 activators remains a significant challenge. The discovery of novel and potential small synthetic molecules that modulate Nur77 activity will facilitate therapeutic interventions of Nur77 against several human diseases. In this study, we have reported the development of a novel and effective Nur77 ligand. Our data show that (1E,4E)-1,5-di(pyrazin-2-yl)penta-1,4-dien-3-one (PB) induces Nur77 transcriptional activity by interacting with a putative Nur77 ligand binding site by forming solid hydrogen bonding. Calculated chemical parameters denote that PB has sophisticated chemical features that will enhance its interaction with the Nur77 ligand-binding domain. Molecular docking simulations showed that PB fits in the Nur77 putative ligand binding site with solid hydrogen bonding, and molecular dynamics simulations indicate that PB binding would stabilize the Nur77 ligand binding domain. Further, in vitro studies revealed that PB increases Nur77 nuclear expression and activity, inhibits cigarette smoke-induced inflammatory phenotype of airway epithelial cells, and protects against apoptosis. These findings provide insights into developing an effective Nur77 small-molecule activator which could be developed into a therapeutic agent against inflammatory diseases.
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