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

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.