Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening.
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.
Markt
Patrick
P
Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
McGoohan
Caroline
C
Walker
Brian
B
Kirchmair
Johannes
J
Feldmann
Clemens
C
De Martino
Gabriella
G
Spitzer
Gudrun
G
Distinto
Simona
S
Schuster
Daniela
D
Wolber
Gerhard
G
Laggner
Christian
C
Langer
Thierry
T
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
D004791:Enzyme Inhibitors; D008024:Ligands; D002403:Cathepsins; C028217:cathepsin S