Anti-gout activity and the interaction mechanisms between Sanghuangporus vaninii active components and xanthine oxidase

• Published in: Bioorganic chemistry 2023-04, Vol.133, p.106394-106394, Article 106394
• Main Authors: Song, Jiling, Wang, Zhanwei, Chi, Yu, Zhang, Yong, Fang, Chenyi, Shu, Yuting, Cui, Jing, Bai, Helong, Wang, Jing
• Format: Article
• Language: English
• Subjects: Basidiomycota - chemistry; Davallialactone; Enzyme Inhibitors - chemistry; Gout - drug therapy; Humans; IL-1β; Molecular docking; Molecular Docking Simulation; Sanghuangporus vaninii; TNF-α; Xanthine oxidase; Xanthine Oxidase - drug effects
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106394

[Display omitted] •A key enzyme in gout disease progression, XO, is inhibited by davallialactone.•In vitro experiments support molecular docking simulations of XO inhibition.•Davallialactone reduces TNF-α and IL-1β in gout cells and is non-toxic at 21.55 μM.•Hydrophobic interactions and hydrogen bonds are critical in binding. Xanthine oxidase (XO) plays a critical role in the progression of gout. We showed in a previous study that Sanghuangporus vaninii (S. vaninii), a perennial, medicinal, and edible fungus traditionally used to treat various symptoms, contains XO inhibitors. In the current study, we isolated an active component of S. vaninii using high performance countercurrent chromatography and identified it as davallialactone using mass spectrometry with 97.726 % purity. A microplate reader showed that davallialactone had mixed inhibition of XO activity with a half-inhibitory concentration value of 90.07 ± 2.12 μM. In addition, the collision between davallialactone and XO led to fluorescence quenching and conformational changes in XO, which were mainly driven by hydrophobicity and hydrogen bonding. Molecular simulations further showed that davallialactone was located at the center of the molybdopterin (Mo-Pt) of XO and interacted with amino acid residues Phe798, Arg912, Met1038, Ala1078, Ala1079, Gln1194, and Gly1260, suggesting that entering the enzyme-catalyzed reaction was unfavorable for the substrate. We also observed face-to-face π-π interactions between the aryl ring of davallialactone and Phe914. Cell biology experiments indicated that davallialactone reduced the expression of the inflammatory factors, tumor necrosis factor alpha and interleukin-1 beta (P