4P6E

Crystal Structure of Human Cathepsin S Bound to a Non-covalent Inhibitor

Summary for 4P6E

• Entry DOI: 10.2210/pdb4p6e/pdb
• Descriptor: Cathepsin S, SULFATE ION, N-[(8R)-8-(benzoylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]-4-methylpiperazine-1-carboxamide, ... (4 entities in total)
• Functional Keywords: cysteine protease, cathepsin s, inhibitor, non-covalent, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Lysosome: P25774
• Total number of polymer chains: 2
• Total formula weight: 52176.42

Authors

Wang, Y.,Jadhav, P.K.,Deng, G.G. (deposition date: 2014-03-24, release date: 2014-10-29, Last modification date: 2024-10-30)

Primary citation

Jadhav, P.K.,Schiffler, M.A.,Gavardinas, K.,Kim, E.J.,Matthews, D.P.,Staszak, M.A.,Coffey, D.S.,Shaw, B.W.,Cassidy, K.C.,Brier, R.A.,Zhang, Y.,Christie, R.M.,Matter, W.F.,Qing, K.,Durbin, J.D.,Wang, Y.,Deng, G.G.
Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm.
Acs Med.Chem.Lett., 5:1138-1142, 2014

PubMed Abstract: Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.

PubMed: 25313327
DOI: 10.1021/ml500283g

Experimental method

X-RAY DIFFRACTION (1.8 Å)