Discovery a series of novel inhibitors of human dihydroorotate dehydrogenase: Biological activity evaluation and molecular docking

  • Chem Biol Drug Des. 2023 Nov 5. doi: 10.1111/cbdd.14388.
Xiaoli Ren  1 ,  Xiaoyong Liu  1 ,  Miao Hua  2 ,  Yan Dai  1 ,  Xiaoping Ren  1 ,  Chaoya Sui  1 ,  Xiangbi Li  3 ,  Zhiyong Jiang  1 ,  Min Tian  4 ,  Bing Yang  1
Affiliations
  • 1. College of Environment and Quality Inspection, Chongqing Chemical Industry Vocational College, Chongqing, China.
  • 2. Chongqing Experimental School, Chongqing, China.
  • 3. Chongqing Auleon Biologicals Co., Ltd, Chongqing, China.
  • 4. College of Pharmacy, Chongqing University of Arts and Sciences, Chongqing, China.
PMID: 37926553 DOI: 10.1111/cbdd.14388
Abstract

Human Dihydroorotate Dehydrogenase (hDHODH) is a key enzyme that catalyzes the de novo synthesis of pyrimidine. In recent years, various studies have shown that inhibiting this enzyme can treat autoimmune diseases such as rheumatoid arthritis (RA) and Cancer. This study designed and synthesized a series of novel thiazolidone hDHODH inhibitors. Through biological activity evaluation, Compound 14 was found to have high inhibitory activity, with an IC50 value reaching nanomolar level. Preliminary structure-activity relationship studies found that the carboxyl group in R1 and the naphthalene in R2 are key factors in improving activity. Through molecular docking, the binding mode between inhibitors and proteins was elucidated. This study provides an important reference for further optimizing hDHODH inhibitors.

Keywords
biological activity evaluation; human dihydroorotate dehydrogenase (hDHODH); inhibitor; molecular docking; rheumatoid arthritis.
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