Identification of novel 11b-HSD1 inhibitors by combined ligand- and structure-based virtual screening
Author
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Lagos, Carlos F.
Author
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Vecchiola, Andrea
es_CL
Author
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Allende, Fidel
es_CL
Author
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Fuentes, Cristóbal A.
es_CL
Author
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Tichauer, Juan E.
es_CL
Author
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Valdivia, Carolina
es_CL
Author
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Solari, Sandra
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Author
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Campino, Carmen
es_CL
Author
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Tapia Castillo, Alejandra
es_CL
Author
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Baudrand, René
es_CL
Author
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Villarroel, Pia
es_CL
Author
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Cifuentes, Mariana
es_CL
Author
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Owen, Gareth I.
es_CL
Author
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Carvajal, Cristian A.
es_CL
Author
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Fardella, Carlos E.
Admission date
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2015-01-05T19:45:52Z
Available date
dc.date.available
2015-01-05T19:45:52Z
Publication date
dc.date.issued
2014
Cita de ítem
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Molecular and Cellular Endocrinology 384 (2014) 71–82
en_US
Identifier
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DOI:
Identifier
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https://repositorio.uchile.cl/handle/2250/124146
General note
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Artículo de publicación ISI
en_US
Abstract
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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.