Xanthine oxidase (XO) is a molybdopterin-containing enzyme that performs the interconversion of xanthine to uric acid within the last step of the purine catabolism in the human body. High blood concentrations of uric acid can lead to gout and hyperuricemia. Therefore, drugs that inhibit the biosynthesis or increase the secretion of uric acid by human XO have been clinically used for many years to decrease the concentration of uric acid in the blood. In this work, by employing the molecular dynamics, and hybrid quantum mechanics/molecular mechanics calculations, we have investigated the interaction between the active site of the XO and a new promising drug, FYX-051, to investigate the reaction mechanism of this inhibitor with the XO at the atomic and electronic structure level. Results on the structural and dynamical effects of FYX-051, as well as the calculated reaction mechanism for the first oxidation step catalyzed by the molybdopterin center in the active site will be presented and discussed.

QM/MM studies of xanthine oxidase inhibitors

ACS Spring 2022

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