Identification of novel 11β-HSD1 inhibitors by combined ligand- and structure-based virtual screening.
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.
['Lagos|Carlos F|CF|', 'Vecchiola|Andrea|A|', 'Allende|Fidel|F|', 'Fuentes|Cristobal A|CA|', 'Tichauer|Juan E|JE|', 'Valdivia|Carolina|C|', 'Solari|Sandra|S|', 'Campino|Carmen|C|', 'Tapia-Castillo|Alejandra|A|', 'Baudrand|Rene|R|', 'Villarroel|Pia|P|', 'Cifuentes|Mariana|M|', 'Owen|Gareth I|GI|', 'Carvajal|Cristian A|CA|', 'Fardella|Carlos E|CE|']
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 D017667:Adipocytes D002454:Cell Differentiation D045744:Cell Line, Tumor D055808:Drug Discovery D004791:Enzyme Inhibitors D015870:Gene Expression D006801:Humans D006854:Hydrocortisone D007700:Kinetics D008024:Ligands D062105:Molecular Docking Simulation D013329:Structure-Activity Relationship D014584:User-Computer Interface
11β-HSD1 inhibitor Virtual screening Metabolic syndrome 11β-hydroxysteroid dehydrogenase type 1 HPLC-MS/MS cortisol determination LS14 cells