The role of fluorine in stabilizing the bioactive conformation of dihydroorotate dehydrogenase inhibitors

Silvia Bonomo, Paolo Tosco, Marta Giorgis, Marco Lolli, Roberta Fruttero

Research output: Contribution to journalJournal articleResearchpeer-review


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.
Original languageEnglish
JournalJournal of Molecular Modeling
Issue number3
Pages (from-to)1099-1107
Number of pages9
Publication statusPublished - 2013
Externally publishedYes


  • Enzyme Inhibitors
  • Fluorine
  • Models, Molecular
  • Molecular Docking Simulation
  • Oxadiazoles
  • Oxidoreductases Acting on CH-CH Group Donors
  • Pyrimidines
  • dihydroorotate dehydrogenase
  • Physical and Theoretical Chemistry
  • Computer Science Applications
  • Computational Theory and Mathematics
  • Catalysis
  • Organic Chemistry
  • Inorganic Chemistry
  • Bioactive conformation
  • DHODH inhibitor
  • PES scan
  • Strain energy
  • brequinar
  • dihydroorotate dehydrogenase inhibitor
  • fluorine
  • leflunomide
  • article
  • atom
  • conformation
  • drug activity
  • drug potency
  • drug stability
  • drug structure
  • fluorination
  • molecular docking
  • priority journal
  • substitution reaction
  • Chemistry
  • Computer Applications in Chemistry
  • Molecular Medicine
  • Computer Appl. in Life Sciences
  • Characterization and Evaluation of Materials
  • Theoretical and Computational Chemistry
  • Chemistry and Materials Science
  • MODE

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