Dual binding mode of a novel series of DHODH inhibitors.
Article Details
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Baumgartner R, Walloschek M, Kralik M, Gotschlich A, Tasler S, Mies J, Leban J
Dual binding mode of a novel series of DHODH inhibitors.
J Med Chem. 2006 Feb 23;49(4):1239-47.
- PubMed ID
- 16480261 [ View in PubMed]
- Abstract
Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Dihydroorotate dehydrogenase (quinone), mitochondrial Q02127 Details - Binding Properties