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中文摘要：
蛋白激酶A（PKA）和蛋白激酶C（PKC）的过度表达导致细胞生长分化异常,是治疗肿瘤的潜在靶点.抑制剂BD2对PKA和PKC抑制作用存在高选择性.为了探讨BD2高选择性机制,本工作以PKA与BD2复合物的晶体结构为模板,通过同源模建结合分子对接的方法构建PKCβII与BD2复合物的结构,并对PKA-BD2复合物和PKC-BD2复合物进行了2.5ns的分子动力学模拟,运用MM-GBSA方法计算了结合自由能,通过能量分解的方法考察PKA和PKC的主要残基与BD2之间的相互作用和识别机制.结合能分析结果很好地描述了BD2对PKA抑制活性比其对PKC抑制活性高这一实验现象.氢键分析和能量分解结果共同说明了BD2的B环和酰胺链部分与PKA和PKC中相应位点的残基之间的相互作用存在差异,这是BD2存在选择性的内在因素.BD2高选择性作用机制的阐明为进一步基于结构的balanol类抑制剂的结构设计和优化提供了合理的指导.
英文摘要：
Protein kinase A （PKA） and protein kinase C （PKC） are potential targets in treating tumour and their over expression leads to cellular proliferation and differentiation abnormally. BD2 is a high selective inhibitor for PKA over PKC. In order to elucidate the mechanism of the high selectivity of BD2, in this paper, using the crystal structure of PKA complexed with BD2 as the template, model of PKC βⅡ was built by homology modeling and its complex with BD2 was constructed by molecular docking. 2.5 ns molecular dynamics simulations were carried out on PKA-BD2 complex and PKC-BD2 complex. The binding energy of BD2 with PKA and PKC was calculated by MM-GBSA method, and the interaction between BD2 with the key residues of the two protein kinases was evaluated by energy decomposition analysis. The result of binding energy can described the experimental phenomenon that BD2 is high selective inhibitor for PKA over PKC. The difference of the interaction of B ring and acidamide of BD2 with PKA and PKC was evaluated by hydrogen bond analysis and energy decomposition analysis, which is intrinsic factor for selectivity of BD2. The mechanism of the high selectivity of BD2 was elucidated, which provides the basis for designing and optimizing balanol analogue inhibitor.
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