Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP.
Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP.
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DOI：
10.1016/j.ejmech.2009.11.054
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发表时间：
2010-04
影响因子：
6.7
通讯作者：
Wagner, Carston R.
中科院分区：
文献类型：
--
作者：
Jia, Yan;Chiu, Ting-Lan;Amin, Elizabeth A.;Polunovsky, Vitaly;Bitterman, Peter B.;Wagner, Carston R.
在癌症的发展中经常观察到帽依赖性翻译的异常调节。帽结合蛋白eIF 4 E与N7-甲基化鸟苷加帽mRNA的结合是控制翻译起始的限速步骤;因此代表了癌症药物发现的有吸引力的过程。以前，已经发现用苄基取代Me 7-鸟苷一磷酸的7-Me基团增加对eIF 4 E的结合亲和力。最近的X射线晶体学研究表明，帽依赖口袋经历了独特的结构变化，以适应苄基。为了探索控制N7-苄基化鸟苷一磷酸（Bn 7-GMP）对eIF 4 E的亲和力的结构活性关系，我们利用如在Schrodinger®中实施的CombiGlide虚拟地筛选了80种Bn 7-GMP类似物的文库。合成取代的Bn 7-GMP类似物的子集文库，并测定它们的解离常数（Kd）。由于对接/评分结果与实验结合亲和力之间的相关性较差，因此进行了三维定量结构-活性关系（3D-QSAR）计算。推导并优化了两个具有高度预测性和自洽性的CoMFA（比较分子场分析）和CoMSIA（比较分子相似性指数分析）模型。这些模型可能是有用的eIF 4 E帽结合拮抗剂的未来设计。
Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap binding protein eIF4E with N7-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me7-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-dependent pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure activity relationships governing the affinity of N7- benzylated guanosine monophosphate (Bn7-GMP) for eIF4E, we virtually screened a library of 80 Bn7-GMP analogs utilizing CombiGlide as implemented in Schrodinger®. A subset library of substituted Bn7-GMP analogs was synthesized and their dissociation constants (Kd) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.
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影响因子：
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作者：
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通讯作者：
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