4BS5

MOUSE CATHEPSIN S WITH COVALENT LIGAND

4BS5 の概要

• エントリーDOI: 10.2210/pdb4bs5/pdb
• 関連するPDBエントリー: 4BQV 4BS6 4BSQ
• 分子名称: CATHEPSIN S, (2S,4R)-N-[1-(iminomethyl)cyclopropyl]-4-[2-(trifluoromethyl)phenyl]sulfonyl-pyrrolidine-2-carboxamide (3 entities in total)
• 機能のキーワード: hydrolase, cysteine protease, covalent ligand
• 由来する生物種: MUS MUSCULUS (HOUSE MOUSE)
• 細胞内の位置: Lysosome: O70370
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25051.87

構造登録者

Banner, D.W.,Benz, J.,Gsell, B.,Stihle, M.,Ruf, A.,Haap, W. (登録日: 2013-06-07, 公開日: 2013-11-27, 最終更新日: 2024-10-16)

主引用文献

Hilpert, H.,Mauser, H.,Humm, R.,Anselm, L.,Kuehne, H.,Hartmann, G.,Gruener, S.,Banner, D.W.,Benz, J.,Gsell, B.,Kuglstatter, A.,Stihle, M.,Thoma, R.,Alvarez-Sanchez, R.,Iding, H.,Wirz, B.,Haap, W.
Identification of Potent and Selective Cathepsin S (Cats) Inhibitors Containing Different Central Cyclic Scaffolds.
J.Med.Chem., 56:9789-, 2013

PubMed Abstract: Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.

PubMed: 24224654
DOI: 10.1021/JM401528K

実験手法

X-RAY DIFFRACTION (1.25 Å)