title: Pharmacophore Model Refinement for 11β-Hydroxysteroid Dehydrogenase Inhibitors: Search for Modulators of Intracellular Glucocorticoid Concentrations.
abstract: 11β-Hydroxysteroid dehydrogenases (11β-HSD) control the intracellular concentrations of glucocorticoids: 11β-HSD1 converts the inactive cortisone to the active cortisol, and 11β-HSD2 is responsible for the opposite reaction. Inhibition of 11β-HSD1 is beneficial in the treatment of metabolic syndrome, whereas 11β-HSD2 inhibition leads to hypertension. Therefore, 11β-HSD1 inhibitors should be selective over 11β-HSD2. To support drug discovery and toxicological studies, we have previously reported pharmacophore models for 11β-HSD1 and 2 inhibition. These models represent the common chemical features of 11β-HSD inhibitors, which were used as virtual screening filter. Since new inhibitors are constantly discovered, the quality of the pharmacophore models has to be evaluated in order to maintain a good predictive power. In this study, we report a systematic evaluation and refinement of our pharmacophore model collection. We employed our models for virtual screening, especially focusing on the 11β-HSD2 inhibition. In total, 42 compounds were biologically evaluated and among these we discovered 17 11β-HSD inhibitors that decreased the residual enzyme activity to 50% or less at the concentration of 20 µM. The experimental 11β-HSD1 and 2 readouts from these compounds were used for further model refinement. Evaluation metrics were applied for a quantitative comparison of the old and newly generated models which resulted in a set of improved pharmacophore models offering reliable in silico tools for the identification of novel and selective 11β-HSD inhibitors.
authors.affiliation: Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria phone/fax: +43 512 507 58253/+43 512 507 58299.
authors.forename: Anna
authors.initials: A
authors.lastname: Vuorinen
authors.affiliation: Swiss Center of Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Lyubomir G
authors.initials: LG
authors.lastname: Nashev
authors.affiliation: Swiss Center of Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.affiliation: Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
authors.affiliation: Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria phone/fax: +43 512 507 58253/+43 512 507 58299. Daniela.Schuster@uibk.ac.at.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
keywords: 11β-Hydroxysteroid dehydrogenase; Enzyme inhibitor; Model refinement; Pharmacophore model; Virtual screening