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Pharmacophore Model Refinement for 11β-Hydroxysteroid Dehydrogenase Inhibitors: Search for Modulators of Intracellular Glucocorticoid Concentrations.
Journal article

Pharmacophore Model Refinement for 11β-Hydroxysteroid Dehydrogenase Inhibitors: Search for Modulators of Intracellular Glucocorticoid Concentrations.

  • Vuorinen A 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.
  • Nashev LG 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.
  • Odermatt A 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.
  • Rollinger JM Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck - CMBI, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria.
  • Schuster D 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.
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  • 2016-08-04
Published in:
  • Molecular informatics. - 2014
11β-Hydroxysteroid dehydrogenase
Enzyme inhibitor
Model refinement
Pharmacophore model
Virtual screening
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/299183
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