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

Human 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.