Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors

被引：58

作者：

Antonysamy, Stephen S. ^{[1
]}

Aubol, Brandon ^{[1
]}

Blaney, Jeff ^{[1
]}

Browner, Michelle F. ^{[2
]}

Giannetti, Anthony M. ^{[2
]}

Harris, Seth F. ^{[2
]}

Hebert, Normand ^{[1
]}

Hendle, Joerg ^{[1
]}

Hopkins, Stephanie ^{[1
]}

Jefferson, Elizabeth ^{[1
]}

Kissinger, Charles ^{[1
]}

Leveque, Vincent ^{[2
]}

Marciano, David ^{[1
]}

McGee, Ethel ^{[1
]}

Najera, Isabel ^{[2
]}

Nolan, Brian ^{[1
]}

Tomimoto, Masaki ^{[1
]}

Torres, Eduardo ^{[1
]}

Wright, Tobi ^{[1
]}

机构：

[1] SGX Pharmaceut Inc, Med Chem, San Diego, CA 92121 USA

[2] Roche Palo Alto, Palo Alto, CA 94304 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 09期

关键词：

HCV; NS5b; fragment screening; protein crystallography;

D O I：

10.1016/j.bmcl.2008.03.056

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with similar to 1-10 mM binding affinity (K-D) were iteratively optimized to give leads with similar to 200 nM biochemical activity and low mu M cellular activity in a Replicon assay. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：2990 / 2995

页数：6

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