Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening

被引：18

作者：

Markt, Patrick ^{[1
,2
]}

McGoohan, Caroline ^{[3
]}

Walker, Brian ^{[3
]}

Kirchmair, Johannes ^{[1
,2
,4
]}

Feldmann, C. Lemens ^{[1
,2
]}

De Martino, Gabriella ^{[5
]}

Spitzer, Gudrun ^{[6
]}

Distinto, Simona

Schuster, Daniela ^{[1
,2
,4
]}

Wolber, Gerhard ^{[4
]}

Laggner, Christian ^{[1
,2
]}

Langer, Thierry ^{[1
,2
,4
]}

机构：

[1] Univ Innsbruck, Dept Pharmaceut Chem, Inst Pharm, A-6020 Innsbruck, Austria

[2] Univ Innsbruck, Ctr Mol Biosci, A-6020 Innsbruck, Austria

[3] Queens Univ Belfast, Sch Pharm, Belfast BT9 7BL, Antrim, North Ireland

[4] Inte Ligand Softwareentwicklungs & Consulting Gmb, A-2344 Maria Enzersdorf, Austria

[5] Univ Rome, Fac Farm, I-00185 Rome, Italy

[6] Univ Innsbruck, Inst Gen Inorgan & Theoret Chem, Dept Theoret Chem, A-6020 Innsbruck, Austria

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2008年 / 48卷 / 08期

关键词：

D O I：

10.1021/ci800101j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The cysteine protease cathepsin S (CatS) is involved in the pathogenesis of autoimmune disorders, atherosclerosis, and obesity. Therefore, it represents a promising pharmacological target for drug development. We generated ligand-based and structure-based pharmacophore models for noncovalent and covalent CatS inhibitors to perform virtual high-throughput screening of chemical databases in order to discover novel scaffolds for CatS inhibitors. An in vitro evaluation of the resulting 15 structures revealed seven CatS inhibitors with kinetic constants in the low micromolar range. These compounds can be subjected to further chemical modifications to obtain drugs for the treatment of autoimmune disorders and atherosclerosis.

引用

页码：1693 / 1705

页数：13

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