Discovery of a New Class of Thiazolidin-4-one-Based Inhibitors of Human Dihydroorotate Dehydrogenase: Biological Activity Evaluation, Molecular Docking, and Molecular Dynamics.

The continuous outbreak of various viruses reminds us to prepare broad-spectrum antiviral drugs. Human dihydroorotate dehydrogenase (hDHODH) inhibitor exhibits broad-spectrum antiviral effects. In order to explore the novel type of human dihydroorotate dehydrogenase inhibitor (hDHODHi), we have optimized, designed, and synthesized 17 compounds and conducted biological activity evaluation, molecular docking, and molecular dynamics studies. The results of biological activity evaluation showed that compounds 10 and 16 exhibited submicromolar inhibitory activity, with IC(50) values of 0.188 ± 0.004 and 0.593 ± 0.012 μM, respectively. Molecular docking studies showed that compounds 10 and 16 were in good agreement with the hDHODH activity pocket and interacted well with amino acid residues. Compared to the cocrystallized structure of the brequinar analogue complex, inhibitors 10 and 16 increased their direct interaction with Ala55. In addition, molecular dynamics studies showed that inhibitors 10 and 16 have strong affinity for proteins, and their complexes are stable, which confirms the significant inhibitory effect of inhibitors 10 and 16 on hDHODH in vitro. Through analysis, it was found that the carboxyl group and para introduced fluorine atoms in R (1), as well as the naphthalene in R (2), are key factors in improving activity. This conclusion provides help for further research into hDHODH inhibitors in the future. This study has promoted the significance of the development of broad-spectrum antiviral drugs.