A novel series of human dihydroorotate dehydrogenase inhibitors discovered by in vitro screening: inhibition activity and crystallographic binding mode. Issue 8 (29th May 2019)

• Record Type: Journal Article
• Authors: Zeng, Ting; Zuo, Zeping; Luo, Youfu; Zhao, Yinglan; Yu, Yamei; Chen, Qiang
• Is Part Of: FEBS open bio. Volume 9:Issue 8(2019)
• Page Start: 1348
• Page End: 1354
• Publication Date: 2019-05-29
• Subjects: crystal structure -- dihydroorotate dehydrogenase -- drug -- inhibitor -- pyrimidine biosynthesis; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.12658
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : Human dihydroorotate dehydrogenase (DHODH), the enzyme that catalyzes the rate‐limiting step in de novo pyrimidine biosynthesis, is considered to be an attractive target for potential treatment of autoimmune disease and cancer. Here, we present a novel class of human DHODH inhibitors with high inhibitory potency. The high‐resolution crystal structures of human DHODH complexed with various agents reveal the details of their interactions. Comparisons with the binding modes of teriflunomide and brequinar provide insights that may facilitate the development of new inhibitors targeting human DHODH. Abstract : We have discovered a novel class of human dihydroorotate dehydrogenase (DHODH) inhibitors with high inhibitory potency by in vitro screening. The high‐resolution crystal structures and comparisons with other inhibitors provide insights that may facilitate the development of new inhibitors targeting human DHODH.