title: Different inhibitory potency of febuxostat towards mammalian and bacterial xanthine oxidoreductases: insight from molecular dynamics.
abstract: Febuxostat, a drug recently approved in the US, European Union and Japan for treatment of gout, inhibits xanthine oxidoreductase (XOR)-mediated generation of uric acid during purine catabolism. It inhibits bovine milk XOR with a K(i) in the picomolar-order, but we found that it is a much weaker inhibitor of Rhodobacter capsulatus XOR, even though the substrate-binding pockets of mammalian and bacterial XOR are well-conserved as regards to catalytically important residues and three-dimensional structure, and both permit the inhibitor to be accommodated in the active site, as indicated by computational docking studies. To clarify the reason for the difference of inhibitory potency towards the two XORs, we performed molecular dynamics simulations. The results indicate that differences in mobility of hydrophobic residues that do not directly interact with the substrate account for the difference in inhibitory potency.
authors.affiliation: Department of Physics, Nippon Medical School, 2-297-2 Kosugi-cho, Nakahara-Ku, Kawasaki 211-0063, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujisaki
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Furuta
authors.forename: Ken
authors.initials: K
authors.lastname: Okamoto
authors.forename: Silke
authors.initials: S
authors.lastname: Leimkühler
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishino
mesh_terms: D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000069465:Febuxostat; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016354:Rhodobacter capsulatus / Q000201:enzymology; D013844:Thiazoles / Q000494:pharmacology*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D013844:Thiazoles; D000069465:Febuxostat; D014968:Xanthine Dehydrogenase