The discovery of new 11beta-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening.
11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the conversion of biologically inactive 11-ketosteroids into their active 11beta-hydroxy derivatives and vice versa. Inhibition of 11beta-HSD1 has considerable therapeutic potential for glucocorticoid-associated diseases including obesity, diabetes, wound healing, and muscle atrophy. Because inhibition of related enzymes such as 11beta-HSD2 and 17beta-HSDs causes sodium retention and hypertension or interferes with sex steroid hormone metabolism, respectively, highly selective 11beta-HSD1 inhibitors are required for successful therapy. Here, we employed the software package Catalyst to develop ligand-based multifeature pharmacophore models for 11beta-HSD1 inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed several selective inhibitors. Efficient inhibition of recombinant human 11beta-HSD1 in intact transfected cells as well as endogenous enzyme in mouse 3T3-L1 adipocytes and C2C12 myotubes was demonstrated for compound 27, which was able to block subsequent cortisol-dependent activation of glucocorticoid receptors with only minor direct effects on the receptor itself. Our results suggest that inhibitor-based pharmacophore models for 11beta-HSD1 in combination with suitable cell-based activity assays, including such for related enzymes, can be used for the identification of selective and potent inhibitors.
Schuster
Daniela
D
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52c, Austria.
Maurer
Evelyne M
EM
Laggner
Christian
C
Nashev
Lyubomir G
LG
Wilckens
Thomas
T
Langer
Thierry
T
Odermatt
Alex
A
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D006854:Hydrocortisone / Q000502:physiology; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000235:genetics; D012984:Software; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D004791:Enzyme Inhibitors; D008024:Ligands; D011965:Receptors, Glucocorticoid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone