Discovery of Novel 11β-HSD1 Inhibitors by Pharmacophore-Based Virtual Screening

摘要

The 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1) enzyme is involved in modulation of glucocorticoid activity within target tissues. This enzyme may contribute to obesity and/or metabolic disease through its action in adipose or liver tissue. Inhibition of 11β-HSD1 has major therapeutic potential for glucocorticoid-associated diseases, including obesity, diabetes (wound healing), and muscle atrophy. To develop such therapeutics, we performed a pharmacophore-based virtual screening (VS) for identification of novel 11β-HSD1 inhibitors and found that the VS hit compounds show potent inhibition of 11β-HSD1 enzyme activity. Further, we present a binding model for active compounds. The proposed pharmacophore may serve as a useful guideline for future design of new chemical entities as 11β-HSD1-targeted antidiabetic agents.