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.
Keywords: crystal structure; dihydroorotate dehydrogenase; drug; inhibitor; pyrimidine biosynthesis.
© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.