TITLE:
Correlation of docking energies with spectroscopic kinetic assays of potential xanthine oxidase substrates
AUTHORS:
Amy L. Stockert, Tarek M. Mahfouz, Brad Petersen, Oluwaseun L. Fakunmoju
KEYWORDS:
Xanthine Oxidase; Computer Modeling; Docking; Inhibitor Design; Active Site Model
JOURNAL NAME:
Journal of Biophysical Chemistry,
Vol.4 No.1,
February
28,
2013
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.