Identification of novel anti-inflammatory Nur77 modulators by virtual screening

Orphan nuclear receptor Nur77 is a unique member of the NR4A nuclear receptor subfamily, which is critical for cellular processes especially the inflammatory responses. Many efforts have been made to discover novel scaffold small molecules targeting Nur77. Herein, we evaluated the previously reported binding sites in crystal structures of Nur77 with small molecules, and then discovered compound 13 as a hit of Nur77 via virtual screening targeting the best-scored binding site. Based on the results of fluorescence titration assay, structure-activity relationship (SAR) analysis was summarized for compound 13 and its analogs. Among these analogs, compound 13e displayed the most potent binding affinity (0.54 ± 0.02 μM). The binding mode of compound 13e was predicted via molecule docking. Moreover, 13e exhibited significant anti-inflammation activity in TNF-α induced HepG2 cell model. Taken together, these results provided a new insight into the understanding the functions of specific binding sites on Nur77 for small molecular compounds, and the development of new scaffold Nur77 modulators.