Pharmacophore model refinement for 11β-hydroxysteroid dehydrogenase inhibitors: Search for modulators of intracellular glucocorticoid concentrations

Abstract: 11b-Hydroxysteroid dehydrogenases (11b-HSD)control the intracellular concentrations of glucocorticoids:11b-HSD1 converts the inactive cortisone to the active cortisol,and 11b-HSD2 is responsible for the opposite reaction. Inhibition of 11b-HSD1 is beneficial in the treatment of metabolic syndrome, whereas 11b-HSD2 inhibition leads to hypertension. Therefore, 11b-HSD1 inhibitors should be selective over 11b-HSD2. To support drug discovery and toxicological studies, we have previously reported pharmacophoremodels for 11b-HSD1 and 2 inhibition. These models represent the common chemical features of 11b-HSD inhibitors, which were used as virtual screening filter. Since new inhibitors are constantly discovered, the quality of the pharmacophore models has to be evaluated in order to maintain a good predictive power. In this study, we report a systematic evaluation and refinement of our pharmacophore model collection. We employed our models for virtual screening, especially focusing on the 11b-HSD2 inhibition. In total, 42 compounds were biologically evaluated and among these we discovered 17 11b-HSD inhibitors that decreased the residual enzyme activity to 50% or less at the concentration of 20 mM. The experimental 11b-HSD1 and 2 readouts from these compounds were used for further model refinement. Evaluation metrics were applied for a quantitative comparison of the old and newly generated models which resulted in a set of improved pharmacophore models offering reliable in silico tools for the identification of novel and selective 11b-HSD inhibitors.