Investigation of the Inhibition Mechanism of Xanthine Oxidoreductase by Oxipurinol: A Computational Study

Xanthine oxidoreductase (XOR) is
an enzyme found in various organisms.
It converts hypoxanthine to xanthine and urate, which are crucial
steps in purine elimination in humans. Elevated uric acid levels can
lead to conditions like gout and hyperuricemia. Therefore, there is
significant interest in developing drugs that target XOR for treating
these conditions and other diseases. Oxipurinol, an analogue of xanthine,
is a well-known inhibitor of XOR. Crystallographic studies have revealed
that oxipurinol directly binds to the molybdenum cofactor (MoCo) in
XOR. However, the precise details of the inhibition mechanism are
still unclear, which would be valuable for designing more effective
drugs with similar inhibitory functions. In this study, molecular
dynamics and quantum mechanics/molecular mechanics calculations are
employed to investigate the inhibition mechanism of XOR by oxipurinol.
The study examines the structural and dynamic effects of oxipurinol
on the pre-catalytic structure of the metabolite-bound system. Our
results provide insights on the reaction mechanism catalyzed by the
MoCo center in the active site, which aligns well with experimental
findings. Furthermore, the results provide insights into the residues
surrounding the active site and propose an alternative mechanism for
developing alternative covalent inhibitors.