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理論生物物理と生化学を組み合わせた薬効研究―キサンチン酸化還元酵素と阻害剤フェブキソスタットの結合機序
藤崎 弘士1,2, 古田 忠臣3, 岡本 研4, 菊地 浩人1
1日本医科大学基礎科学物理学
2理化学研究所次世代計算科学研究開発プログラム分子スケール研究開発チーム
3東京工業大学大学院生命理工学研究科生体分子機能工学専攻
4日本医科大学生化学・分子生物学
Combined Biophysical and Biochemical Study of Enzyme Effects: Binding Mechanism of an Inhibitor Febuxostat with Xanthine Oxidoreductase
Hiroshi Fujisaki1,2, Tadaomi Furuta3, Ken Okamoto4 and Hiroto Kikuchi1
1)Department of Physics, Nippon Medical School
2)Computational Science Research Program, RIKEN
3)Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology
4)Department of Biochemistry, Nippon Medical School
We review our recent collaborative study, performed by computational physicists and biochemists, of the enzyme effects due to the drug called febuxostat. Febuxostat, which was 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. Experiments have shown that febuxostat has strong effects on mammalian XOR but not on bacterial XOR, although the two enzymes have similar three-dimensional structures. To clarify the difference in the inhibitory power of febuxostat, we performed docking and molecular dynamics simulations for mammalian and bacterial XORs. We found that the static structures are not sufficient to explain the binding difference and that important interactions occur between febuxostat and the active region of the enzymes which suggests a better strategy for drug design.
日医大医会誌 2012; 8(3), 222-227
Key words
xanthine oxidoreductase, inhibitor, molecular dynamics, docking, binding free energy
Correspondence to
Hiroshi Fujisaki, Department of Physics, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
E-mail：fujisaki@nms.ac.jp
受付：2012年3月29日 受理：2012年4月27日 |
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