人类二氢乳酸醛酸脱氢酶（hDHODH）是许多疾病的有前途的药物靶点，包括自身免疫性疾病、癌症和病毒感染。为了开发更多新型、更有效的hDHODH抑制剂，我们筛选了我们内部的旧药物库。我们发现，甲状腺激素代谢产物三碘甲状腺酸（tiratricol）具有强的hDHODH抑制活性（IC50:0.754±0.126μM），其前体四碘甲状腺酸（tetrac）也对hDHODH显示一定的抑制活性（IC50:11.960±1.453μM）。酶动力学分析表明，tiratricol和tetrac与CoQ0是无竞争性抑制剂，这与阳性对照A771726有所不同。热力FMN测定、分子对接和定点突变分析均表明，tiratricol和tetrac与hDHODH的关键残基相互作用比A771726更多，尤其是在次位点1中的一些疏水残基。总之，我们的实验结果表明了旧药物tiratricol的潜在新用途，并为设计hDHODH抑制剂提供了新的化学支架。©2023 John Wiley & Sons Ltd.

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.© 2023 John Wiley & Sons Ltd.