ArticleACS catalysis2023
Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat.
Article in ACS catalysis, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
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- Comparing Force Field Treatments in QM/MM Studies of the SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp) Mechanism.Journal of chemical theory and computation · 2025Article
- Machine-learning and simulation identify food-derived xanthine oxidase inhibitors with in-vitro activity.Scientific reports · 2025Article
- Comparison of Magnesium and Manganese Ions on the Structural and Catalytic Properties of Human DNA Polymerase Gamma.Journal of chemical theory and computation · 2025Article
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- Cardiovascular Events During Treatment With Xanthine Oxidoreductase Inhibitors in Patients With Gout and Hyperuricemia in Japan - A JMDC Claims Database Study.Circulation reports · 2025Article
- Inhibitory Activity of Quercetin, Rutin, and Hyperoside against Xanthine Oxidase: Kinetics, Fluorescence, and Molecular Docking.Current pharmaceutical biotechnology · 2025Article
- CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ.Journal of chemical information and modeling · 2024Article
- An interaction network in the polymerase active site is a prerequisite for Watson-Crick base pairing in Pol γ.Science advances · 2024Article
- Drug Repositioning via Graph Neural Networks: Identifying Novel JAK2 Inhibitors from FDA-Approved Drugs through Molecular Docking and Biological Validation.Molecules (Basel, Switzerland) · 2024Article
- Using deep learning and molecular dynamics simulations to unravel the regulation mechanism of peptides as noncompetitive inhibitor of xanthine oxidase.Scientific reports · 2024Article
- Investigation of the Inhibition Mechanism of Xanthine Oxidoreductase by Oxipurinol: A Computational Study.Journal of chemical information and modeling · 2023Article
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Funding
Abstract
Xanthine oxidase (XO) is a member of the molybdopterin-containing enzyme family. It interconverts xanthine to uric acid as the last step of purine catabolism in the human body. The high uric acid concentration in the blood directly leads to human diseases like gout and hyperuricemia. Therefore, drugs that inhibit the biosynthesis 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 study, the inhibition mechanism of XO and a new promising drug, topiroxostat (code: FYX-051), is investigated by employing molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. This drug has been reported to act as both a noncovalent and covalent inhibitor and undergoes a stepwise inhibition by all its hydroxylated metabolites, which include 2-hydroxy-FYX-051, dihydroxy-FYX-051, and trihydroxy-FYX-051. However, the detailed mechanism of inhibition of each metabolite remains elusive and can be useful for designing more effective drugs with similar inhibition functions. Hence, herein we present the computational investigation of the structural and dynamical effects of FYX-051 and the calculated reaction mechanism for all of the oxidation steps catalyzed by the molybdopterin center in the active site. Calculated results for the proposed reaction mechanisms for each metabolite's inhibition reaction in the enzyme's active site, binding affinities, and the noncovalent interactions with the surrounding amino acid residues are consistent with previously reported experimental findings. Analysis of the noncovalent interactions via energy decomposition analysis (EDA) and noncovalent interaction (NCI) techniques suggests that residues L648, K771, E802, R839, L873, R880, R912, F914, F1009, L1014, and A1079 can be used as key interacting residues for further hybrid-type inhibitor development.
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