The Discovery of New llbeta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors by Common Feature Pharmacophore Modeling and Virtual Screening

摘要

11 beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the conversion of biologically inactive 11-ketosteroids into their active ll beta-hydroxy derivatives and vice versa.Inhibition of 11 beta-HSD1 has considerable therapeutic potential for glucocorticoid-associated diseases including obesity,diabetes,wound healing,and muscle atrophy.Because inhibition of related enzymes such as 11 beta-HSD2 and 17 beta-HSDs causes sodium retention and hypertension or interferes with sex steroid hormone metabolism,respectively,highly selective 11 beta-HSD1 inhibitors are required for successful therapy.Here,we employed the software package Catalyst to develop ligand-based multifeature pharmacophore models for l1 beta-HSDl inhibitors.Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed several selective inhibitors.Efficient inhibition of recombinant human 11 beta-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 11 beta-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.