title: The role of fluorine in stabilizing the bioactive conformation of dihydroorotate dehydrogenase inhibitors.
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.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonomo
authors.forename: Paolo
authors.initials: P
authors.lastname: Tosco
authors.forename: Marta
authors.initials: M
authors.lastname: Giorgis
authors.forename: Marco
authors.initials: M
authors.lastname: Lolli
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
mesh_terms: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000737:chemistry; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis / Q000737:chemistry
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011743:Pyrimidines; D005461:Fluorine; D044925:Oxidoreductases Acting on CH-CH Group Donors