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Investigation of the interaction between Chrysoeriol and xanthine oxidase using computational and in vitro approaches
Yan Liu1, Chenggang Han1, Tao Lu1
1School of Chemical Engineering, Sichuan University, Chengdu 610065, China.
Abstract:
Xanthine oxidase (XO) plays a vital role in inducing hyperuricemia and increasing the level of superoxide free radicals in blood, and is proved as an important target for gout. Chrysoeriol (CHE) is a natural flavone with potent XO inhibitory activity (IC50 = 2.487 ± 0.213 μM), however, the mechanism of interaction is still unclear. Therefore, a comprehensive analysis of the interaction between CHE and XO was accomplished by enzyme kinetics, isothermal titration calorimetry (ITC), multi-spectroscopic methods, molecular simulation and ADMET. The results showed that CHE acted as a rapid reversible and competitive-type XO inhibitor and its binding to XO was driven by hydrogen bonding and hydrophobic interaction. Moreover, CHE exhibited a strong fluorescence quenching effect through a static quenching procedure and induced conformational changes of XO. Its binding pattern with XO was revealed by docking study and the binding affinity to XO was enhanced by the interactions with key amino acid residues in the active pocket of XO. Further, CHE showed good stability and pharmacokinetic behavior properties in molecule dynamic simulation and ADMET prediction. Overall, this study shed some light on the mechanism of interaction between CHE and XO, also provided some valuable information concerning the future therapeutic application of CHE as natural XO inhibitor.
Insights
Chrysoeriol (CHE) is a potent xanthine oxidase (XO) inhibitor, acting competitively by binding through hydrogen bonds and hydrophobic interactions. This natural flavone shows promise for treating gout by reducing hyperuricemia.
Area of Science:
- Biochemistry
- Pharmacology
- Natural Products Chemistry
Background:
- Xanthine oxidase (XO) is a key enzyme in purine metabolism, implicated in hyperuricemia and gout pathogenesis.
- Chrysoeriol (CHE), a natural flavone, exhibits significant XO inhibitory activity, but its interaction mechanism requires elucidation.
Purpose of the Study:
- To comprehensively analyze the interaction mechanism between Chrysoeriol (CHE) and Xanthine Oxidase (XO).
- To evaluate the potential of CHE as a therapeutic agent for gout and hyperuricemia.
Main Methods:
- Enzyme kinetics, isothermal titration calorimetry (ITC), and multi-spectroscopic methods were employed.
- Molecular docking, molecular dynamics simulations, and ADMET predictions were utilized to assess binding and pharmacokinetic properties.
Main Results:
- CHE functions as a rapid, reversible, competitive inhibitor of XO.
- Binding is driven by hydrogen bonding and hydrophobic interactions, with CHE inducing conformational changes in XO.
- Molecular simulations and ADMET predictions indicate good stability and favorable pharmacokinetic behavior for CHE.
Conclusions:
- CHE effectively inhibits XO through specific interactions within the enzyme's active pocket.
- The findings support the potential therapeutic application of Chrysoeriol as a natural xanthine oxidase inhibitor for managing hyperuricemia and gout.
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