MOLECULAR DYNAMICS AND FREE ENERGY ANALYSIS OF XANTHINE OXIDOREDUCTASE- LIGAND INTERACTIONS H. Kikuchi1, H. Fujisaki 1, 2, T. Furuta3, K. Okamoto4, and T. Nishino5
1Department of Physics, Nippon Medical School, 2-297-2, Kosugi-cho, Nakahara-ku,
2Computational Science Research Program, RIKEN, 2-1 Hirosawa,
3Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology,
B-62 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, JAPAN
4Department of Biochemistry, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku,
5Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi,
ABSTRACT TEXT Xanthine oxidoreductase (XOR) is an enzyme which is found in a wide range of organisms from bacteria to man and plays an important role in the catabolism of purine substrates. In mammals and birds, XOR physiologically catalyzes the hydroxylation of hypoxanthine to xanthine, followed by the catalysis of the hydroxylation of xanthine to uric acid. As the excessive production of uric acid leads to gout and hyperuricemia, human XOR is a target of drugs for these diseases. Febuxostat is one of ligands in XOR, and fills up most of the cavity of XOR without being covalently bound to it1). Febuxostat has been developed as a non-purine selective inhibitor of XOR, showing a more potent and longer-lasting urate-lowering effect than allopurinol which is another XOR inhibitor, widely prescribed as a treatment of gout and hyperuricemia for more than 40 years. Clinical efficacy and tolerance to febuxostat have been confirmed, and the drug is available as Adenuric (EU), Uloric (US), or Feburic (Japan). In our previous work2), we experimentally found that, among human, bovine, and bacterial XORs whose 3D structures are known thus far, the bacterial XOR from Rhodobacter capsulutus was only very weakly inhibited by febuxostat, whereas the mammalian XORs were strongly inhibited. These findings are in contrast to the case of allopurinol, which is covalently bound to all the XORs, and is equally effective on all of them. These facts indicate that the binding mechanism of febuxostat in the substrate-binding pocket is different between the bacterial XOR and mammalian XORs, even though the important residues for catalysis are all conserved and there is enough space for febuxostat to enter the binding pocket of the bacterial XOR. Thus, to clarify the reason for the difference of inhibitory potency towards the two XORs, we performed molecular dynamics simulations, and pointed out the importance of some amino acids residues near the entrance of the cavity in XOR.
In the present work, we discuss the binding mechanism between XOR and fubuxostat
more precisely using free energy calculations, employing different types of drugs or mutated XORs.
1) K. Okamoto et al., J. Biol. Chem. 278, 1848–1855 (2003). 2) H. Kikuchi et al.,Sci. Rep.2, 331; DOI:10.1038/srep00331 (2012).
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