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

E-mail: skahn@incheon.ac.krReceived March 21, 2012, Accepted April 23, 2012The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme is involved in modulation of glucocorti-coid activity within target tissues. This enzyme may contribute to obesity and/or metabolic disease through itsaction 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 thera-peutics, we performed a pharmacophore-based virtual screening (VS) for identification of novel 11β-HSD1inhibitors and found that the VS hit compounds show potent inhibition of 11 β-HSD1 enzyme activity. Further,we present a binding model for active compounds. The proposed pharmacophore may serve as a usefulguideline for future design of new chemical entities as 11 β-HSD1-targeted antidiabetic agents. Key Words : 11β-HSD1, Pharmacophore-based virtual screening, Antidiabetic, Glucocorticoid, Moleculardocking IntroductionIn Cushing’s syndrome, the notable excess of glucocorti-coids causes metabolic abnormalities, such as visceral obesity,impaired glucose tolerance, atherosclerosis, dyslipidemia,and hyperglycemia.