Artículos de revistas
Identification of novel 11b-HSD1 inhibitors by combined ligand- and structure-based virtual screening
Fecha
2014Registro en:
Molecular and Cellular Endocrinology 384 (2014) 71–82
DOI:
Autor
Lagos, Carlos F.
Fardella, Carlos E.
Vecchiola, Andrea
Allende, Fidel
Fuentes, Cristóbal A.
Tichauer, Juan E.
Valdivia, Carolina
Solari, Sandra
Campino, Carmen
Tapia Castillo, Alejandra
Baudrand, René
Villarroel, Pia
Cifuentes, Mariana
Owen, Gareth I.
Carvajal, Cristian A.
Institución
Resumen
11 beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) converts cortisone to cortisol in a NADPH
dependent manner. Overexpression of 11b-HSD1 in key metabolic tissues is related to the development
of type 2 diabetes, obesity, hypertension and metabolic syndrome. Using crystal structures of human
11b-HSD1 in complex with inhibitors as source of structural information, a combined ligand and structure-
based virtual screening approach was implemented to identify novel 11b-HSD1 inhibitors. A
selected group of compounds was identified in silico and further evaluated in cell-based assays for cytotoxicity
and 11b-HSD1 mediated cortisol production inhibitory capacity. The expression of 11b-HSD1 and
11b-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
11b-HSD1 mediated cortisol production inhibitory activity with potencies in the micromolar range. Two
compounds showed to be selective for the 11b-HSD1 reductase activity and over 11b-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.