Escuela de Ingeniería en Bioinformática, Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
Curr Pharm Des. 2012;18(20):2946-63. doi: 10.2174/138161212800672705.
Protein kinases (PKs) are key components of protein phosphorylation based signaling networks in eukaryotic cells. They have been identified as being implicated in many diseases. High-resolution X-ray crystallographic data exist for many PKs and, in many cases, these structures are co-complexed with inhibitors. Although this valuable information confirms the precise structure of PKs and their complexes, it ignores the dynamic movements of the structures which are relevant to explain the affinities and selectivity of the ligands, to characterize the thermodynamics of the solvated complexes, and to derive predictive models. Atomistic molecular dynamics (MD) simulations present a convenient way to study PK-inhibitor complexes and have been increasingly used in recent years in structure-based drug design. MD is a very useful computational method and a great counterpart for experimentalists, which helps them to derive important additional molecular information. That enables them to follow and understand structure and dynamics of protein-ligand systems with extreme molecular detail on scales where motion of individual atoms can be tracked. MD can be used to sample dynamic molecular processes, and can be complemented with more advanced computational methods (e.g., free energy calculations, structure-activity relationship analysis). This review focuses on the most commonly applications to study PK-inhibitor complexes using MD simulations. Our aim is that researchers working in the design of PK inhibitors be aware of the benefits of this powerful tool in the design of potent and selective PK inhibitors.
蛋白激酶（PKs）是真核细胞中基于蛋白质磷酸化的信号转导网络的关键组成部分。它们已被确定与许多疾病有关。许多 PK 都有高分辨率的 X 射线晶体学数据，在许多情况下，这些结构与抑制剂共同复合。尽管这些有价值的信息证实了 PK 及其复合物的精确结构，但它忽略了结构的动态运动，这些运动对于解释配体的亲和力和选择性、描述溶剂化复合物的热力学以及得出预测模型是相关的。原子分子动力学（MD）模拟为研究 PK-抑制剂复合物提供了一种便捷的方法，近年来在基于结构的药物设计中得到了越来越多的应用。MD 是一种非常有用的计算方法，也是实验人员的绝佳搭档，它可以帮助他们得出重要的额外分子信息。这使他们能够以极端分子细节跟踪和理解蛋白质-配体系统的结构和动力学，在单个原子运动可以被追踪的尺度上。MD 可用于采样动态分子过程，并可与更先进的计算方法（例如自由能计算、结构-活性关系分析）相结合。本综述重点介绍了使用 MD 模拟研究 PK-抑制剂复合物的最常见应用。我们的目的是让从事 PK 抑制剂设计的研究人员意识到这种强大工具在设计有效和选择性 PK 抑制剂方面的优势。
