Chalcones from plants cause toxicity by inhibiting human and rat 11β-hydroxysteroid dehydrogenase 2: 3D-quantitative structure-activity relationship (3D-QSAR) and in silico docking analysis.
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association(2023)
摘要
Chalcones from licorice and its related plants have many pharmacological effects. However, the effects of chalcones on the activity of human and rat 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), and associated side effects remain unclear. The inhibition of 11 chalcones on human and rat 11β-HSD2 were evaluated in microsomes and a 3D-quantitative structure-activity relationship (3D-QSAR) was analyzed. Screening revealed that bavachalcone, echinatin, isobavachalcone, isobavachromene, isoliquiritigenin, licochalcone A, and licochalcone B significantly inhibited human 11β-HSD2 with IC50 values ranging from 15.62 (licochalcone A) to 38.33 (echinatin) μM. Screening showed that the above chemicals and 4-hydroxychalcone significantly inhibited rat 11β-HSD2 with IC50 values ranging from 6.82 (isobavachalcone) to 72.26 (4-hydroxychalcone) μM. These chalcones acted as noncompetitive/mixed inhibitors for both enzymes. Comparative analysis revealed that inhibition of 11β-HSD2 depended on the species. Most chemicals bind to the NAD+ binding site or both the NAD+ and substrate binding sites. Bivariate correlation analysis showed that lipophilicity and molecular weight determine inhibitory strength. Through our 3D-QSAR models, we identified that the hydrophobic region, hydrophobic aliphatic groups, and hydrogen bond acceptors are pivotal factors in inhibiting 11β-HSD2. In conclusion, many chalcones inhibit human and rat 11β-HSD2, possibly causing side effects and there is structure-dependent and species-dependent inhibition on 11β-HSD2.
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