Structure-based de novo design of Eya2 phosphatase inhibitors
Structure-based de novo design of Eya2 phosphatase inhibitors
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DOI：
10.1016/j.jmgm.2012.05.003
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发表时间：
2012-09-01
影响因子：
2.9
通讯作者：
Kim, Seung Jun
中科院分区：
文献类型：
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作者：
Park, Hwangseo;Ryu, Seong Eon;Kim, Seung Jun
虽然Eyes缺失蛋白酪氨酸磷酸酶被一系列有说服力的实验证据证明与多种人类癌症有关，但迄今为止只有很少数量的小分子抑制剂被报道。我们已经能够通过基于结构的从头设计与两个已知的抑制剂支架，包含一个适当的螯合基团的活性位点Mg2+离子，确定29个新的抑制剂的眼睛缺乏同源物2（Eya 2）。由于这些新发现的抑制剂被筛选为具有理想的物理化学性质作为候选药物，并表现出中等的抑制活性，IC 50值范围为6至50 μ M，它们值得考虑进一步研究，以开发新的抗癌药物。详细讨论了与Eya 2磷酸酶活性位点中所识别的抑制剂的稳定相关的结构特征。(C)2012 Elsevier Inc. All rights reserved.
Although Eyes absent protein tyrosine phosphatases proved to be involved in various human cancers by a series of persuasive experimental evidence, only a very few number of small-molecule inhibitors have been reported so far. We have been able to identify 29 novel inhibitors of Eyes absent homologue 2 (Eya2) by means of a structure-based de novo design with the two known inhibitor scaffolds that contain a proper chelating group for the active-site Mg2+ ion. Because these newly found inhibitors were screened for having desirable physicochemical properties as a drug candidate and exhibited a moderate inhibitory activity with IC50 values ranging from 6 to 50 mu M, they deserve consideration for further investigation to develop new anticancer medicines. Structural features relevant to the stabilization of the identified inhibitors in the active site of Eya2 phosphatase are discussed in detail. (C) 2012 Elsevier Inc. All rights reserved.