4P6G

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

4P6G の概要

• エントリーDOI: 10.2210/pdb4p6g/pdb
• 関連するPDBエントリー: 4P6E
• 分子名称: Cathepsin S, (3R,4S)-4-[(4-fluorobenzoyl)amino]-6-[4-(oxetan-3-yl)piperazin-1-yl]-3,4-dihydro-2H-chromen-3-yl methylcarbamate (3 entities in total)
• 機能のキーワード: cathespsin s, non-covalent inhibitor, cysteine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Lysosome: P25774
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 102478.64

構造登録者

Wang, Y.,Jadhav, P.K. (登録日: 2014-03-24, 公開日: 2014-10-29, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.58 Å)