Computational Insight into p21-Activated Kinase 4 Inhibition: A Combined Ligand- and Structure- Based Approach
Computational Insight into p21-Activated Kinase 4 Inhibition: A Combined Ligand- and Structure- Based Approach
复制标题
p21 激活激酶 4 抑制的计算见解：基于配体和结构的组合方法
DOI：
10.1002/cmdc.201400016
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发表时间：
2014-05-01
期刊：
影响因子：
3.4
通讯作者：
Cheng, Mao-Sheng
中科院分区：
文献类型：
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作者：
Li, Rui-Juan;Wang, Jian;Cheng, Mao-Sheng
p21-Activated kinase 4 （PAK4）是一种丝氨酸/苏氨酸蛋白激酶，在包括癌症在内的多种人类疾病中发挥重要作用。用特异性抑制剂靶向这种激酶在癌症治疗中具有很大的兴趣。在本研究中，通过结合配体和结构的方法研究了PAK4及其与atp竞争抑制剂的相互作用。首先，建立了一个基于配体的药效团模型，该模型由五个化学特征组成：一个正离子中心、两个疏水性基团、一个氢键供体和一个氢键受体，这与现有的SAR信息一致。活性位点的特征随后被描述为一个拓扑区域，并用于对接九种选定的抑制剂。药效团模型和对接研究结果的结合使我们能够权衡各种药效团的特征，并确定正离子可电离中心是一个间隔点，而不是一个基本点。该研究提出了PAK4活性位点内的相互作用模型，并为设计更有效的PAK4抑制剂提供了指导。
p21-Activated kinase 4 (PAK4) is a serine/threonine protein kinase that plays important roles in a wide variety of human diseases including cancer. Targeting this kinase with specific inhibitors is of great interest in the treatment of cancer. In this study, PAK4 and its interaction with ATP-competitive inhibitors was investigated by a combined ligand- and structure-based approach. First, a ligand-based pharmacophore model was generated, consisting of five chemical features: a positive ionizable center, two hydrophobic groups, a hydrogen bond donor, and a hydrogen bond acceptor, which is consistent with available SAR information. The characteristics of the active site were then described as a topological region and used in docking of nine selected inhibitors. Combination of the pharmacophore model and results from the docking studies allowed us to weigh the various pharmacophore features and to identify the positive ionizable center as a spacer rather than an essential point. This research led to the proposal of an interaction model inside the PAK4 active site and provided guidance for the design of more potent PAK4 inhibitors.