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Different inhibitory potency of febuxostat towards mammalian and bacterial xanthine oxidoreductases: insight from molecular dynamics
- 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.
Author details: | Hiroto Kikuchi, Hiroshi Fujisaki, Tadaomi Furuta, Ken Okamoto, Silke LeimkühlerORCiDGND, Takeshi Nishino |
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DOI: | https://doi.org/10.1038/srep00331 |
ISSN: | 2045-2322 |
Title of parent work (English): | SCIENTIFIC REPORTS |
Publisher: | NATURE PUBLISHING GROUP |
Place of publishing: | LONDON |
Publication type: | Article |
Language: | English |
Year of first publication: | 2012 |
Publication year: | 2012 |
Release date: | 2017/03/26 |
Volume: | 2 |
Number of pages: | 8 |
Funding institution: | KAKENHI [16205021, 23570198, 22540421]; Ministry of Education, Culture, Sports, Science and Technology (MEXT); Deutsche Forschungsgemeinschaft |