A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy.
A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy.
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DOI：
10.1021/jm801475n
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发表时间：
2009-04-23
影响因子：
7.3
通讯作者：
Hunter WN
中科院分区：
文献类型：
--
作者：
Ramsden NL;Buetow L;Dawson A;Kemp LA;Ulaganathan V;Brenk R;Klebe G;Hunter WN
在革兰氏阴性细菌和顶端复合体寄生虫中，非甲戊酸合成异戊二烯的途径是必不可少的。这一途径的酶在哺乳动物中是缺失的，这有助于它们成为化疗靶点。一种名为2C-甲基-D-赤藓糖醇-2，4-环二磷酸合成酶(ISPF)的酶已被细菌中的遗传学方法证实为靶标。采用分层筛选与分子对接相结合的方法，对大肠杆菌ISPF(EcIspF)进行了虚拟筛选。对接的化合物进行了检查，并选择了10种进行实验验证。建立了表面等离子体共振分析方法，确定了两个弱配体。确定了ECIspF配合物的晶体结构，以支持合理的配体开发。对胞嘧啶类似物和锌离子结合部分进行了表征。其中一个可能与锌离子结合的化合物测得的Kd值最低(1.92±0.18μM)。这些数据为开发ISPF抑制剂提供了一个框架，以产生具有治疗潜力的抗微生物病原体的先导化合物。
The nonmevalonate route to isoprenoid biosynthesis is essential in Gram-negative bacteria and apicomplexan parasites. The enzymes of this pathway are absent from mammals, contributing to their appeal as chemotherapeutic targets. One enzyme, 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), has been validated as a target by genetic approaches in bacteria. Virtual screening against Escherichia coli IspF (EcIspF) was performed by combining a hierarchical filtering methodology with molecular docking. Docked compounds were inspected and 10 selected for experimental validation. A surface plasmon resonance assay was developed and two weak ligands identified. Crystal structures of EcIspF complexes were determined to support rational ligand development. Cytosine analogues and Zn2+-binding moieties were characterized. One of the putative Zn2+-binding compounds gave the lowest measured KD to date (1.92 ± 0.18 μM). These data provide a framework for the development of IspF inhibitors to generate lead compounds of therapeutic potential against microbial pathogens.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
--
作者：
Borza, T;Popescu, CE;Lee, RW
通讯作者：
Lee, RW
影响因子：
16.6
作者：
Crane, CM;Kaiser, J;Diederich, F
通讯作者：
Diederich, F
影响因子：
--
作者：
Buetow, Lori;Brown, Amanda C.;Hunter, William N.
通讯作者：
Hunter, William N.
DOI：
10.1107/s0907444994003112
发表时间：
1994-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
BAILEY, S
通讯作者：
BAILEY, S