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Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase.
Cao, Shuying; Ma, Hui; Xu, Zhaomin; Fang, Wenqing; Huang, Jin; Huang, Ying.
Afiliação
  • Cao S; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • Ma H; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • Xu Z; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • Fang W; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • Huang J; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • Huang Y; Drug Inspection Technology, Guangdong Institute for Drug Control, Guangzhou, China.
Chem Biol Drug Des ; 102(1): 1-13, 2023 07.
Article em En | MEDLINE | ID: mdl-37088711
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases atuantes sobre Doadores de Grupo CH-CH / Di-Hidro-Orotato Desidrogenase Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases atuantes sobre Doadores de Grupo CH-CH / Di-Hidro-Orotato Desidrogenase Idioma: En Ano de publicação: 2023 Tipo de documento: Article