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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. November 2004, Volume 3, Number 11, 684-703 |
Inhibition of Xanthine-Oxidase by 2,4-Dihydroxy-Benzophenone
and 2,3,4-Trihydroxy-Benzophenone
Gabriela T. Castro, Sonia E. Blanco, and Ferdinando H. Ferretti
Internet Electron. J. Mol. Des. 2004, 3, 684-703
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Abstract:
Xanthine oxidase is a very important enzyme that catalyzes the
oxidation of xanthine to uric acid, which plays a crucial role in
gout. The search for new compounds that are capable of
inhibiting the activity of XO therefore constitutes a field of
investigation that attracts great interest. As a continuation of
studies performed on benzophenones, in this work we determine
the inhibition of XO by 2,4-dihydroxybenzophenone and 2,3,4-trihydroxybenzophenone.
We propose a model for the
representation of the active site of XO, which was used to
describe the possible enzyme-substrate and enzyme-inhibitor
interactions. The IC50 of the compounds was determined using a
UV-visible spectroscopic kinetic method. Basis sets at B3LYP/6-31+G(d)
and HF/3-21G were used for performing the
calculations that permitted to describe the interactions involving
the enzyme, the substrate and the inhibitors. The IC50 data
obtained indicate that 2,4-dihydroxybenzophenone and 2,3,4-trihydroxybenzophenone
exert a moderate inhibiting activity on
XO, which is comparable to that exhibited by other polyphenolic
BPs, but is lower to that of potent inhibitors of XO like
allopurinol or quercetin. On the other hand, a model for the
active site of XO was proposed, which includes a
pentaheteroatomic ring and two extracyclic heteroatoms (S and
O). The structures of the enzyme-substrate and enzyme-inhibitor-complex
were calculated using this model. The inhibition of XO
by 2,4-dihydroxybenzophenone and 2,3,4-trihydroxybenzophenone
is produced by a Michaelis-Menten
mechanism of the competitive reversible type. It was also
established that the inhibiting activity of the compounds is
determined by the stability of the enzyme-inhibitor complex and
is independent of their acidity constants.
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