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The role of fluorine in stabilizing the bioactive conformation of dihydroorotate dehydrogenase inhibitors.
- Source :
-
Journal of molecular modeling [J Mol Model] 2013 Mar; Vol. 19 (3), pp. 1099-107. Date of Electronic Publication: 2012 Nov 10. - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Dihydroorotate Dehydrogenase
Enzyme Inhibitors metabolism
Fluorine metabolism
Models, Molecular
Molecular Docking Simulation
Oxadiazoles chemistry
Oxidoreductases Acting on CH-CH Group Donors chemistry
Oxidoreductases Acting on CH-CH Group Donors metabolism
Pyrimidines biosynthesis
Pyrimidines chemistry
Enzyme Inhibitors chemistry
Fluorine chemistry
Oxidoreductases Acting on CH-CH Group Donors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0948-5023
- Volume :
- 19
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of molecular modeling
- Publication Type :
- Academic Journal
- Accession number :
- 23143678
- Full Text :
- https://doi.org/10.1007/s00894-012-1643-5