Share This Article:

Correlation of docking energies with spectroscopic kinetic assays of potential xanthine oxidase substrates

Abstract Full-Text HTML XML Download Download as PDF (Size:407KB) PP. 22-27
DOI: 10.4236/jbpc.2013.41003    3,033 Downloads   4,769 Views  

ABSTRACT

Here we present a docking model that ranks compounds according to their potential effectiveness as a potential substrate or inhibitor. We utilize xanthine oxidase (XO), a multi-cofactor oxido-reductase which converts hypoxanthine to xanthine and xanthine to uric acid. During the reductive half reaction, electrons flow from the molybdopterin, to each of two Fe/S centers, and finally to FAD. During the oxidative half reaction, electrons are passed from the FAD to O2. Under ideal physiological conditions, this reduction of oxygen generates H2O2 and, under multiple turnover conditions, superoxide in amounts which is regulated by catalase and superoxide dismutase. Utilizing computer modeling predictions of the docking orientations and energies of a group of purine based structures was selected. Correlating computer estimations with steady state kinetic data, a rapid screening process for inhibittor prediction was highlighted. This method allows educated selection of likely inhibitors, thereby decreasing the time and supplies required to complete a traditional kinetic analysis screening. Results demonstrate the functionality and reliability of this method and have proven particularly useful in understanding binding orienttations or poses of each compound.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Stockert, A. , Mahfouz, T. , Petersen, B. and Fakunmoju, O. (2013) Correlation of docking energies with spectroscopic kinetic assays of potential xanthine oxidase substrates. Journal of Biophysical Chemistry, 4, 22-27. doi: 10.4236/jbpc.2013.41003.

References

[1] Choi, E.Y., Stockert, A.L., Leimkuhler, S. and Hille, R. (2004) Studies on the mechanism of action of xanthine oxidase. Journal of Inorganic Biochemistry, 98, 841-848. doi:10.1016/j.jinorgbio.2003.11.010
[2] Doonan, C.J., Stockert, A., Hille, R. and George, G.N. (2005) Nature of the catalytically labile oxygen at the active site of xanthine oxidase. Journal of the American Chemical Society, 127, 4518-4522. doi:10.1021/ja042500o
[3] Hemann, C., Ilich, P., Stockert, A. L., Choi, E.Y. and Hille, R. (2005) Resonance Raman studies of xanthine oxidase: The reduced enzyme-product complex with violapterin. The Journal of Physical Chemistry B, 109, 3023-3031. doi:10.1021/jp046636k
[4] Hille, R. (1996) The mononuclear molybdenum enzymes. Chemical Reviews, 96, 2757-2816. doi:10.1021/cr950061t
[5] Hille, R. (1997) Mechanistic aspects of the mononuclear molybdenum enzymes. Journal of Biological Inorganic Chemistry, 2, 804-809. doi:10.1007/s007750050199
[6] Huber, R., Hof, P., Duarte, R.O., Moura, J.J.G., Moura, I., Liu, M.Y., LeGall, J., Hille, R., Archer, M. and Romao, M.J. (1996) A structure-based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes. Proceedings of the National Academy of Sciences, 93, 8846-8851. doi:10.1073/pnas.93.17.8846
[7] Kim, J.H., Ryan, M.G., Knaut, H. and Hille, R. (1996) The reductive half-reaction of xanthine oxidase. The involvement of prototropic equilibria in the course of the catalytic sequence. The Journal of Biological Chemistry, 271, 6771-6780.
[8] Okamoto, K., Matsumoto, K., Hille, R., Eger, B.T., Pai, E.F. and Nishino, T. (2004) The crystal structure of xanthine oxidoreductase during catalysis: Implications for reaction mechanism and enzyme inhibition. Proceedings of the National Academy of Sciences, 101, 7931-7936. doi:10.1073/pnas.0400973101
[9] Stockert, A.L., Shinde, S.S., Anderson, R.F. and Hille, R. (2002) The reaction mechanism of xanthine oxidase: Evidence for two-electron chemistry rather than sequential one-electron steps. Journal of the American Chemical Society, 124, 14554-14555. doi:10.1021/ja027388d
[10] Agarwal, A., Banerjee, A. and Banerjee, U.C. (2011) Xanthine oxidoreductase: A journey from purine metabolism to cardiovascular excitation-contraction coupling. Critical Reviews in Biotechnology, 31, 264-280. doi:10.3109/07388551.2010.527823
[11] Akalin, E., Ganeshan, S.V., Winston, J. and Muntner, P. (2008) Hyperuricemia is associated with the development of the composite outcomes of new cardiovascular events and chronic allograft nephropathy. Transplantation, 86, 652-658. doi:10.1097/TP.0b013e3181814f5b
[12] Angelos, M.G., Kutala, V.K., Torres, C.A., He, G.L., Stoner, J.D., Mohammad, M. and Kuppusamy, P. (2006) Hypoxic reperfusion of the ischemic heart and oxygen radical generation. American Journal of Physiology—Heart and Circulatory Physiology, 290, H341-H347. doi:10.1152/ajpheart.00223.2005
[13] Anker, S.D., Doehner, W., Rauchhaus, M., Sharma, R., Francis, D., Knosalla, C., Davos, C.H., Cicoira, M., Shamim, W., Kemp, M., Segal, R., Osterziel, K.J., Leyva, F., Hetzer, R., Ponikowski, P. and Coats, A.J.S. (2003) Uric acid and survival in chronic heart failure—Validation and application in metabolic, functional, and hemodynamic staging. Circulation, 107, 1991-1997. doi:10.1161/01.CIR.0000065637.10517.A0
[14] Becker, L.B., Vanden, H. T.L., Shao, Z.H., Li, C.Q. and Schumacker, P.T. (1999) Generation of superoxide in cardiomyocytes during ischemia before reperfusion. American Journal of Physiology—Heart and Circulatory Physiology, 277, H2240-H2246.
[15] Berry, C.E. and Hare, J.M. (2004) Xanthine oxicloreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. Journal of Physiology (London), 555, 589-606. doi:10.1113/jphysiol.2003.055913
[16] Braunersreuther, V. and Jaquet, V. (2012) Reactive oxygen species in myocardial reperfusion injury: From physiopathology to therapeutic approaches. Current Pharmaceutical Biotechnology, 13, 97-114. doi:10.2174/138920112798868782
[17] Cappola, T.P., Kass, D.A., Nelson, G.S., Berger, R.D., Rosas, G.O., Kobeissi, Z.A., Marban, E. and Hare, J.M. (2001) Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation, 104, 2407-2411. doi:10.1161/hc4501.098928
[18] Coghlan, J.G., Flitter, W.D., Clutton, S.M., Panda, R., Daly, R., Wright, G., Ilsley, C.D. and Slater, T.F. (1994) Allopurinol pretreatment improves postoperative recovery and reduces lipid-peroxidation in patients undergoing coronary-artery bypass-grafting. Journal of Thoracic and Cardiovascular Surgery, 107, 248-256.
[19] Anonymous (1966) Allopurinol for gout. British Medical Journal, 2, 317.
[20] Stockert, A.L. and Stechschulte, M. (2010) Allopurinol to febuxostat: How far have we come? Clinical Medicine Insights: Therapeutics, 2, 927-945.
[21] Fernandez, L., Heredia, N., Grande, L., Gomez, G., Rimola, A., Marco, A., Gelpi, E., Rosello-Catafau, J. and Peralta, C. (2002) Preconditioning protects liver and lung damage in rat liver transplantation: Role of xanthine/ xanthine oxidase. Hepatology, 36, 562-572. doi:10.1053/jhep.2002.34616
[22] Grune, T., Schneider, W. and Siems, W.G. (1993) Reoxygenation injury of rat hepatocytes—Evaluation of nucleotide depletion and oxidative stress as causal components. Cell and Molecular Biology, 39, 635-650.
[23] Kang, S.M., Lim, S., Song, H., Chang, W., Lee, S., Bae, S., Chung, J. H., Lee, H., Kim, H.G., Yoon, D.H., Kim, T.W., Jang, Y., Sung, J.M., Chung, N.S. and Hwang, K.C. (2006) Allopurinol modulates reactive oxygen species generation and Ca2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes. European Journal of Pharmacology, 535, 212-219. doi:10.1016/j.ejphar.2006.01.013
[24] Kinugasa, Y., Ogino, K., Furuse, Y., Shiomi, T., Tsutsui, H., Yamamoto, T., Igawa, O., Hisatome, I. and Shigemasa, C. (2003) Allopurinol improves cardiac dysfunction after ischemia-reperfusion via reduction of oxidative stress in isolated perfused rat hearts. Circulation Journal, 67, 781-787. doi:10.1253/circj.67.781
[25] Lee, J., Hu, Q.S., Mansoor, A., Kamdar, F. and Zhang, J.Y. (2011) Effect of acute xanthine oxidase inhibition on myocardial energetics during basal and very high cardiac workstates. Journal of Cardiovascular Translational Research, 4, 504-513. doi:10.1007/s12265-011-9276-0
[26] Lee, W.Y. and Lee, S.M. (2006) Synergistic protective effect of ischemic preconditioning and allopurinol on ischemia/reperfusion injury in rat liver. Biochemical and Biophysical Research Communications, 349, 1087-1093. doi:10.1016/j.bbrc.2006.08.140
[27] Liu, P.G., He, S.Q., Zhang, Y.H. and Wu, J. (2008) Protective effects of apocynin and allopurinol on ischemia/ reperfusion-induced liver injury in mice. World Journal of Gastroenterology, 14, 2832-2837. doi:10.3748/wjg.14.2832
[28] Matsumoto, F., Sakai, M., Yamaguchi, M., Nakano, H., Matsumiya, A., Kumada, K., Yoshida, K., Shimura, H., Machida, H., Takeuchi, S., Sasaya, S., Midorikawa, T. and Sanada, Y. (1997) Allopurinol reduced hepatic ischemia-reperfusion injury exacerbated by inhalation of high-concentration oxygen in rats. European Surgical Research, 29, 429-437. doi:10.1159/000129554
[29] Mubarak, H.A. (2011) Synergistic effect of ischemic preconditioning, postcoditioning and xanthine oxidase inhibition on cardiac tissue apoptosis of hepatic ischemic-reperfused male rats. Life Science Journal, 8, 253-262.
[30] Peglow, S., Toledo, A.H., Anaya-Prado, R., Lopez-Neblina, F. and Toledo-Pereyra, L.H. (2011) Allopurinol and xanthine oxidase inhibition in liver ischemia reperfusion. Journal of Hepato-Biliary-Pancreatic Sciences, 18, 137-146. doi:10.1007/s00534-010-0328-7
[31] Rhoden, E., Teloken, C., Lucas, M., Rhoden, C., Mauri, M., Zettler, C., Bello-Klein, A. and Barros, E. (2000) Protective effect of allopurinol in the renal ischemia-reperfusion in uninephrectomized rats. General Pharmacology: The Vascular System, 35, 189-193. doi:10.1016/S0306-3623(01)00105-7
[32] Xiao, J., She, Q., Wang, Y., Luo, K.L., Yin, Y.H., Hu, R. and Huang, K.S. (2009) Effect of allopurinol on cardiomyocyte apoptosis in rats after myocardial infarction. European Journal of Heart Failure, 11, 20-27. doi:10.1093/eurjhf/hfn003
[33] (2005) Glide. Schroedinger, LLC.
[34] Zikakis, J.P. and Biasotto, N.O. (1976) Improved Isolation and purification method of xanthine-oxidase from bovine raw whole milk. Abstract of Papers American Chemical Society, 172, 140.
[35] Eger, B.T., Okamoto, K., Enroth, C., Sato, M., Nishino, T., Pai, E.F. and Nishino, T. (2000) Purification, crystallization and preliminary X-ray diffraction studies of xanthine dehydrogenase and xanthine oxidase isolated from bovine milk. Acta Crystallographica Section D, 56, 1656-1658. doi:10.1107/S0907444900012890
[36] Okamoto, K., Eger, B.T., Nishino, T., Kondo, S., Pai, E.F. and Nishino, T. (2003) An extremely potent inhibitor of xanthine oxidoreductase—Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. The Journal of Biological Chemistry, 278, 1848-1855. doi:10.1074/jbc.M208307200
[37] Enroth, C., Eger, B.T., Okamoto, K., Nishino, T., Nishino, T. and Pai, E.F. (2000) Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: Structure-based mechanism of conversion. Proceedings of the National Academy of Sciences, 97, 10723-10728. doi:10.1073/pnas.97.20.10723
[38] Cao, H.N., Pauff, J. and Hille, R. (2011) Substrate orientation and the origin of catalytic power in xanthine oxidoreductase. Indian Journal of Chemistry A, 50, 355-362.

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.