ATP competitive inhibitors of D-alanine-D-alanine ligase based on protein kinase inhibitor scaffolds

被引：40

作者：

Triola, Gemma ^{[1
,2
]}

Wetzel, Stefan ^{[1
,2
]}

Ellinger, Bernhard ^{[1
,2
]}

Koch, Marcus A. ^{[1
,2
]}

Huebel, Katja ^{[1
,2
]}

Rauh, Daniel ^{[1
,3
]}

Waldmann, Herbert ^{[1
,2
]}

机构：

[1] Max Planck Inst Mol Physiol, Dept Biol Chem, D-44227 Dortmund, Germany

[2] Univ Dortmund, Dept Chem, D-44227 Dortmund, Germany

[3] Max Planck Gesell, Chem Genom Ctr, D-44227 Dortmund, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 03期

关键词：

D-Ala-D-ala ligase; Kinase inhibitor; Antibiotics; RECEPTOR TYROSINE KINASE; GROWTH-FACTOR RECEPTOR; ALANYL-D-ALANINE; BIOLOGICAL EVALUATION; POTENT INHIBITOR; T-CELLS; LEFLUNOMIDE; BINDING; TYRPHOSTINS; LFM-A13;

D O I：

10.1016/j.bmc.2008.02.046

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：

D-Alanine-D-alanine ligase (DDl) is an essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons's tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a K-i of 185 mu M. A series of malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1079 / 1087

页数：9

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