Nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S.
The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. Lead optimization afforded potent (IC(50) < 50 nM) and selective inhibitors of CatS demonstrating cellular activity and reversibility of enzyme inhibition.
Thurmond
Robin L
RL
Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
Beavers
Mary Pat
MP
Cai
Hui
H
Meduna
Steven P
SP
Gustin
Darin J
DJ
Sun
Siquan
S
Almond
Harold J
HJ
Karlsson
Lars
L
Edwards
James P
JP
D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000949:Histocompatibility Antigens Class II / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D000949:Histocompatibility Antigens Class II; D007127:Immunoglobulin Constant Regions; D010455:Peptides; D002403:Cathepsins; C028217:cathepsin S