半胱氨酸蛋白酶组织蛋白酶S的非肽类非共价抑制剂。

Nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S.

作者信息

Thurmond Robin L, Beavers Mary Pat, Cai Hui, Meduna Steven P, Gustin Darin J, Sun Siquan, Almond Harold J, Karlsson Lars, Edwards James P

机构信息

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

出版信息

J Med Chem. 2004 Sep 23;47(20):4799-801. doi: 10.1021/jm0496133.

DOI:10.1021/jm0496133

Abstract

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.

摘要

本文描述了半胱氨酸蛋白酶组织蛋白酶S（CatS）的首个非肽类、非共价抑制剂。使用DOCK程序进行电子数据库搜索，生成了一组潜在的CatS抑制剂筛选集，从中确定了两个先导结构，作为药物研发工作的有前景的起始点。先导化合物优化得到了强效（IC(50) < 50 nM）且具有选择性的CatS抑制剂，这些抑制剂显示出细胞活性以及酶抑制的可逆性。

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