Fragment-Based Discovery of BACE1 Inhibitors Using Functional Assays

被引：45

作者：

Godemann, Robert ^{[1
]}

Madden, James ^{[2
]}

Kraemer, Joachim ^{[1
]}

Smith, Myron ^{[2
]}

Fritz, Ulrike ^{[1
]}

Hesterkamp, Thomas ^{[1
]}

Barker, John ^{[2
]}

Hoeppner, Sabine ^{[3
]}

Hallett, David ^{[2
]}

Cesura, Andrea ^{[1
]}

Ebneth, Andreas ^{[1
]}

Kemp, John ^{[1
]}

机构：

[1] Evotec AG, D-22525 Hamburg, Germany

[2] Evotec Ltd, Abingdon OX14 4SA, Oxon, England

[3] Proteros Biostruct GmbH, D-82152 Planegg Martinsried, Germany

来源：

BIOCHEMISTRY | 2009年 / 48卷 / 45期

关键词：

STRUCTURE-BASED DESIGN; X-RAY CRYSTALLOGRAPHY; BETA-SECRETASE; MODEL; BINDING; ENZYME;

D O I：

10.1021/bi901061a

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Novel nonpeptidic inhibitors of beta-secretase (BACE1) have been discovered by employing a fragment-based biochemical screening approach. A diverse library of 20000 low-molecular weight compounds were screened and yielded 26 novel lilts that were confirmed by biochemical and surface plasmon resonance secondary assays. We describe here fragment inhibitors cocrystallized with BACE1 in a flap open and flap closed conformation as determined by X-ray crystallography.

引用

页码：10743 / 10751

页数：9

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