title: Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Caroline
authors.initials: C
authors.lastname: McGoohan
authors.forename: Brian
authors.initials: B
authors.lastname: Walker
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Clemens
authors.initials: C
authors.lastname: Feldmann
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Martino
authors.forename: Gudrun
authors.initials: G
authors.lastname: Spitzer
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
mesh_terms: D002384:Catalysis; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry* / Q000493:pharmacokinetics; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D002403:Cathepsins; C028217:cathepsin S