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

Xanthine oxidoreductase (XOR) isan enzyme found in various organisms.It converts hypoxanthine to xanthine and urate, which are crucialsteps in purine elimination in humans. Elevated uric acid levels canlead to conditions like gout and hyperuricemia. Therefore, there issignificant interest in developing drugs that target XOR for treatingthese conditions and other diseases. Oxipurinol, an analogue of xanthine,is a well-known inhibitor of XOR. Crystallographic studies have revealedthat oxipurinol directly binds to the molybdenum cofactor (MoCo) inXOR. However, the precise details of the inhibition mechanism arestill unclear, which would be valuable for designing more effectivedrugs with similar inhibitory functions. In this study, moleculardynamics and quantum mechanics/molecular mechanics calculations areemployed to investigate the inhibition mechanism of XOR by oxipurinol.The study examines the structural and dynamic effects of oxipurinolon the pre-catalytic structure of the metabolite-bound system. Ourresults provide insights on the reaction mechanism catalyzed by theMoCo center in the active site, which aligns well with experimentalfindings. Furthermore, the results provide insights into the residuessurrounding the active site and propose an alternative mechanism fordeveloping alternative covalent inhibitors.

Automated summary

Xanthine oxidoreductase (XOR) is an enzyme that converts hypoxanthine to xanthine and urate. Inhibitors of XOR, such as oxipurinol, are of interest for developing drugs to treat conditions like gout. This study uses molecular dynamics and quantum mechanics/molecular mechanics calculations to investigate the inhibition mechanism of XOR by oxipurinol, providing insights on the reaction mechanism and proposing alternative mechanisms for developing covalent inhibitors.