Discovery of Novel Cathepsin S Inhibitors by Pharmacophore-Based Virtual High-Throughput Screening

@article{citeulike:3023881, abstract = {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.}, address = {Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria, School of Pharmacy, Queens University Belfast, 97 Lisburn Road, BT9 7BL Belfast, Northern Ireland, Inte:Ligand Softwareentwicklungs- and Consulting GmbH, Clemens Maria Hofbauer-Gasse 6, 2344 Maria Enzersdorf, Austria, Facolta� di Farmacia, Universita di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy, Department of Theoretical Chemistry, Institute of General, Inorganic, and Theoretical Chemistry, University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria, and Dipartimento Farmaco Chimico Tecnologico, Universita� degli Studi di Cagliari, 09124 Cagliari, Italy}, author = {Markt, Patrick and Mcgoohan, Caroline and Walker, Brian and Kirchmair, Johannes and Feldmann, Clemens and Martino, Gabriella D. and Spitzer, Gudrun and Distinto, Simona and Schuster, Daniela and Wolber, Gerhard and Laggner, Christian and Langer, Thierry }, citeulike-article-id = {3023881}, doi = {10.1021/ci800101j}, journal = {J. Chem. Inf. Model.}, keywords = {discovery, drug}, month = {July}, posted-at = {2008-07-21 10:10:04}, priority = {2}, title = {Discovery of Novel Cathepsin S Inhibitors by Pharmacophore-Based Virtual High-Throughput Screening}, url = {http://dx.doi.org/10.1021/ci800101j}, year = {2008} }

TY - JOUR ID - citeulike:3023881 L3 - citeulike-article-id:3023881 TI - Discovery of Novel Cathepsin S Inhibitors by Pharmacophore-Based Virtual High-Throughput Screening JF - J. Chem. Inf. Model. AD - Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria, School of Pharmacy, Queens University Belfast, 97 Lisburn Road, BT9 7BL Belfast, Northern Ireland, Inte:Ligand Softwareentwicklungs- and Consulting GmbH, Clemens Maria Hofbauer-Gasse 6, 2344 Maria Enzersdorf, Austria, Facolta� di Farmacia, Universita di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy, Department of Theoretical Chemistry, Institute of General, Inorganic, and Theoretical Chemistry, University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria, and Dipartimento Farmaco Chimico Tecnologico, Universita� degli Studi di Cagliari, 09124 Cagliari, Italy N2 - 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. KW - discovery KW - drug AU - Markt, Patrick AU - Mcgoohan, Caroline AU - Walker, Brian AU - Kirchmair, Johannes AU - Feldmann, Clemens AU - Martino, Gabriella AU - Spitzer, Gudrun AU - Distinto, Simona AU - Schuster, Daniela AU - Wolber, Gerhard AU - Laggner, Christian AU - Langer, Thierry PY - 2008/07/19/ UR - http://dx.doi.org/10.1021/ci800101j ER -