Identification of chemically diverse Chk1 inhibitors by receptor-based virtual screening
Identification of chemically diverse Chk1 inhibitors by receptor-based virtual screening
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DOI：
10.1016/j.bmc.2006.03.021
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发表时间：
2006-07-15
影响因子：
3.5
通讯作者：
Surgenor, Allan E.
中科院分区：
文献类型：
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作者：
Foloppe, Nicolas;Fisher, Lisa M.;Surgenor, Allan E.
通过小分子抑制Chk 1激酶对于肿瘤学和理解G2/M检查点的细胞调节具有极大的治疗意义。我们报告了大型化合物电子目录与Chk 1 ATP结合位点的X射线结构的计算对接如何允许优先考虑这些化合物的一小部分进行测定。这导致了10种新型Chk 1抑制剂的发现，分布在9种新的和明显不同的化学支架中。这些支架中的几种具有有希望的铅样性质。所有这些配体通过竞争性结合靶向ATP位点而起作用。四个这些化合物结合到这个网站的晶体结构，并提出合理的建模对接模式的其他5个支架。这种结构背景是用来评估这些支架的潜力，进一步药物化学的努力，这表明，其中几个可以详细说明，使额外的相互作用与ATP位点的掩埋部分。一些不寻常的相互作用与保守的激酶骨架基序指出。配体结合模式也被用来讨论其药物化学潜力方面的不希望的化学功能，这些功能是否直接结合到蛋白质。总的来说，这项工作说明了虚拟筛选如何识别一组不同的配体结合到目标位点。这些配体在Chk 1 ATP结合位点的结构模型将有助于进一步靶向这种激酶的药物化学工作。(c)2006爱思唯尔有限公司保留所有权利。
Inhibition of the Chk1 kinase by small molecules is of great therapeutic interest for oncology and in understanding the cellular regulation of the G2/M checkpoint. We report how computational docking of a large electronic catalogue of compounds to an X-ray structure of the Chk1 ATP-binding site allowed prioritisation of a small subset of these compounds for assay. This led to the discovery of 10 novel Chk1 inhibitors, distributed among nine new and clearly different chemical scaffolds. Several of these scaffolds have promising lead-like properties. All these ligands act by competitive binding to the targeted ATP site. The crystal structures of four of these compounds bound to this site are presented, and reasonable modelled docking modes are suggested for the 5 other scaffolds. This structural context is used to assess the potential of these scaffolds for further medicinal chemistry efforts, suggesting that several of them could be elaborated to make additional interactions with the buried part of the ATP site. Some unusual interactions with the conserved kinase backbone motif are pointed out. The ligand-binding modes are also used to discuss their medicinal chemistry potential with respect to undesirable chemical functionalities, whether these functionalities bind directly to the protein or not. Overall, this work illustrates how virtual screening can identify a diverse set of ligands which bind to the targeted site. The structural models for these ligands in the Chk1 ATP-binding site will facilitate further medicinal chemistry efforts targeting this kinase. (c) 2006 Elsevier Ltd. All rights reserved.