Identification of natural xanthine oxidase inhibitors: Virtual screening, anti-xanthine oxidase activity, and interaction mechanism.
Int J Biol Macromol
; 259(Pt 2): 129286, 2024 Feb.
Article
em En
| MEDLINE
| ID: mdl-38216015
ABSTRACT
Xanthine oxidase (XO) is a crucial target for hyperuricemia treatment(s). Naturally occurred XO inhibitors with minimal toxicity and high efficacy have attracted researchers' attention. With the goal of quickly identifying natural XO inhibitors, an integrated computational screening strategy was constructed by molecular docking and calculating the free energy of binding. Twenty-seven hits were achieved from a database containing 19,377 natural molecules. This includes fourteen known XO inhibitors and four firstly-reported inhibitors (isolicoflavonol, 5,7-dihydroxycoumarin, parvifolol D and clauszoline M, IC50 < 40 µM). Iolicoflavonol (hit 8, IC50 = 8.45 ± 0.68 µM) and 5,7-dihydroxycoumarin (hit 25, IC50 = 10.91 ± 0.71 µM) displayed the great potency as mixed-type inhibitors. Docking study and molecular dynamics simulation revealed that both hits could interact with XO's primarily active site residues ARG880, MOS1328, and ASN768 of XO. Fluorescence spectroscopy studies showed that hit 8 bound to the active cavity region of XO, causing changes in XO's conformation and hydrophobicity. Hits 8 and 25 exhibit favorable Absorption, Distribution, Metabolism, and Excretion (ADME) properties. Additionally, no cytotoxicity against human liver cells was observed at their median inhibition concentrations against XO. Therefore, the present study offers isolicoflavonol and 5,7-dihydroxycoumarin with the potential to be disease-modifying agents for hyperuricemia.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Xantina Oxidase
/
Hiperuricemia
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article