Identification of novel 11β-HSD1 inhibitors by combined ligand- and structure-based virtual screening

•11β-HSD1 converts cortisone to cortisol in a NADPH dependent manner.•LS14 adipocyte cell line expressed 11β-HSD1 and not 11β-HSD2 during adipocyte differentiation.•Combined ligand- and structure based virtual screening approach was used to screen the NCI database.•Novel inhibitors selective for 11β-HSD1 reductase activity and over 11β-HSD2 were discovered.

11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to cortisol in a NADPH dependent manner. Overexpression of 11β-HSD1 in key metabolic tissues is related to the development of type 2 diabetes, obesity, hypertension and metabolic syndrome. Using crystal structures of human 11β-HSD1 in complex with inhibitors as source of structural information, a combined ligand and structure-based virtual screening approach was implemented to identify novel 11β-HSD1 inhibitors. A selected group of compounds was identified in silico and further evaluated in cell-based assays for cytotoxicity and 11β-HSD1 mediated cortisol production inhibitory capacity. The expression of 11β-HSD1 and 11β-HSD2 in human LS14 adipocytes was assessed during differentiation. Biological evaluation of 39 compounds in adipocytes and steroids quantification by HPLC-MS/MS identify 4 compounds that exhibit 11β-HSD1 mediated cortisol production inhibitory activity with potencies in the micromolar range. Two compounds showed to be selective for the 11β-HSD1 reductase activity and over 11β-HSD2 isoform, and thus represent novel leads for the development of more active derivatives with higher efficacies targeting intracellular cortisol levels in type 2 diabetes and metabolic syndrome.

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