Molecular Modeling of p38α Mitogen-Activated Protein Kinase Inhibitors through 3D-QSAR and Molecular Dynamics Simulations
Molecular Modeling of p38α Mitogen-Activated Protein Kinase Inhibitors through 3D-QSAR and Molecular Dynamics Simulations
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DOI：
10.1021/ci4000085
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发表时间：
2013-07-01
影响因子：
5.6
通讯作者：
Yang, Chia-Ning
中科院分区：
文献类型：
--
作者：
Chang, Hsin-Wen;Chung, Fu-Sheng;Yang, Chia-Ning
p38 丝裂原激活蛋白激酶 (MAPK) 信号通路在炎症和其他生理过程中发挥着重要作用。由于 p38 α 和 p38 β MAPK 的特异性抑制剂可阻断主要炎症细胞因子和其他蛋白质的产生，因此 p38 α 和 p38 β MAPK 代表了治疗炎症的有希望的靶标。在这项工作中，结合分子建模技术分析了一系列基于 4-苯甲酰基-5-氨基吡唑结构支架的 p38 α 抑制剂。我们为比较分子场分析 (CoMFA) 和比较分子相似性指数分析 (CoMSIA) 生成了三维定量构效关系 (3D-QSAR) 模型，以突出 p38 MAPK 抑制的结构要求。此外，我们采用分子动力学 (MD) 模拟和 MM/GBSA 方法来详细比较有效且选择性的化合物与 p38 α、p38 β、p38 γ 和 p38 delta MAPK 相互作用的结合模式和结合自由能。通过 3D-QSAR 分析生成的等高线图确定了几个关键的相互作用，这些相互作用也通过 MD 模拟表明。通过 MM/GBSA 方法计算的结合自由能与实验观察到的生物活性密切相关，并解释了 p38 α 和 p38 β 的选择性抑制，但不是此处检测到的 p38 γ 和 p38 δ 的选择性抑制。根据所获得的结果，我们提供了有关新型有效 p38 α MAPK 抑制剂开发的见解。
The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in inflammation and other physiological processes. Because specific inhibitors of p38 alpha and p38 beta MAPK block the production of the major inflammatory cytokines and other proteins, p38 alpha and p38 beta MAPK represent promising targets for the treatment of inflammation. In this work, a series of p38 alpha inhibitors based on the structural scaffold of 4-benzoyl-5-aminopyrazole were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for p38 MAPK inhibition. Furthermore, we employed molecular dynamics (MD) simulations and the MM/GBSA method to compare the binding modes and binding free energies of a potent and selective compound interacting with p38 alpha, p38 beta, p38 gamma, and p38 delta MAPK in detail. Contour maps generated via 3D-QSAR analysis identified several key interactions that were also indicated through MD simulations. The binding free energies calculated via the MM/GBSA method were strongly correlated with experimentally observed biological activities and explained the selective inhibition of p38 alpha and p38 beta, but not p38 gamma and p38 delta detected here. On the basis of the obtained results, we provide insights regarding the development of novel potent p38 alpha MAPK inhibitors.