Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase

Abstract

AbstractHuman dihydroorotate dehydrogenase (hDHODH) is a promising drug target for many diseases including autoimmune diseases, cancer, and viral infection. To develop more novel and potent hDHODH inhibitors, we screened our in‐house library of old drugs. We found that tiratricol (3,3′,5‐triiodothyroacetic acid), a thyroid hormone metabolite, has potent hDHODH inhibitory activity (IC50: 0.754 ± 0.126 μM), and its precursor tetrac (3,3′,5,5′‐tetraiodothyroacetic acid) also shows a certain inhibitory activity against hDHODH (IC50: 11.960 ± 1.453 μM). Enzyme kinetic analysis shows that tiratricol and tetrac are noncompetitive inhibitors versus CoQ0, which is different from the positive control A771726. ThermoFMN assay, molecular docking and site‐directed mutagenesis all indicate that tiratricol and tetrac interact with more key residues of hDHODH than A771726, especially some hydrophobic residues in Subsite 1. In conclusion, our experiment results indicate a potential new use for the old drug, tiratricol, and provide a novel chemical scaffold for the design of hDHODH inhibitors.