Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening |
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Authors: | Markt Patrick McGoohan Caroline Walker Brian Kirchmair Johannes Feldmann Clemens De Martino Gabriella Spitzer Gudrun Distinto Simona Schuster Daniela Wolber Gerhard Laggner Christian Langer Thierry |
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Affiliation: | Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria. |
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Abstract: | The cysteine protease cathepsin S (CatS) is involved in the pathogenesis of autoimmune disorders, atherosclerosis, and obesity. Therefore, it represents a promising pharmacological target for drug development. We generated ligand-based and structure-based pharmacophore models for noncovalent and covalent CatS inhibitors to perform virtual high-throughput screening of chemical databases in order to discover novel scaffolds for CatS inhibitors. An in vitro evaluation of the resulting 15 structures revealed seven CatS inhibitors with kinetic constants in the low micromolar range. These compounds can be subjected to further chemical modifications to obtain drugs for the treatment of autoimmune disorders and atherosclerosis. |
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