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The role of fluorine in stabilizing the bioactive conformation of dihydroorotate dehydrogenase inhibitors
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The role of fluorine in stabilizing the bioactive conformation of dihydroorotate dehydrogenase inhibitors
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Journal Article
The role of fluorine in stabilizing the bioactive conformation of dihydroorotate dehydrogenase inhibitors
2013
Overview
Dihydroorotate dehydrogenase (DHODH) is an important drug target due to its prominent role in pyrimidine biosynthesis. Leflunomide and brequinar are two well-known DHODH inhibitors, which bind to the enzyme in the same pocket with different binding modes. We have recently realized a series of new inhibitors based on the 4
-
hydroxy
-
1,2,5
-
oxadiazole ring, whose activity profile was found to be closely dependent on the degree of fluorine substitution at the phenyl ring adjacent to the oxadiazole moiety; a positive influence of fluorine on the DHODH inhibitory potency was observed previously [Baumgartner et al. (
2006
) J Med Chem 49:1239–1247]. Potential energy surface scans showed that fluorine plays an important role in stabilizing the bioactive conformations; additionally, fluorine influences the balance between leflunomide-like and brequinar-like binding modes. These findings may serve as a guide to design more potent DHODH inhibitors.
Publisher
Springer-Verlag,Springer Nature B.V
Subject
/ Characterization and Evaluation of Materials
/ Chemistry and Materials Science
/ Computer Appl. in Life Sciences
/ Computer Applications in Chemistry
/ Dihydroorotate dehydrogenase
/ Enzyme Inhibitors - chemistry
/ Enzyme Inhibitors - metabolism
/ Enzymes
/ Fluorine
/ Ligands
/ Molecular Docking Simulation
/ Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors
/ Oxidoreductases Acting on CH-CH Group Donors - chemistry
/ Oxidoreductases Acting on CH-CH Group Donors - metabolism
/ Proteins
