生物活性分子的结构和相互作用的理论研究

【作者】 张勇；

【导师】 徐顺；

【作者基本信息】 郑州大学 ， 物理化学， 2005， 硕士

【摘要】 全文共分为3个部分:第一部分为利用密度泛函方法研究从天然产物中提取的有效成分——白藜芦醇、柚皮素和洋芹素的结构特征,并用以解释其生物活性;第二部分同样利用密度泛函方法研究尿嘧啶和茶碱分子识别膜的作用机理;第三部分利用分子力学方法研究表皮生长因子受体与其小分子抑制剂之间的相互作用以及α糖苷酶与糖苷酶抑制剂——氨基糖之间的相互作用模式。 第一部分:首先在HF/3-21G水平上搜索顺式和反式白藜芦醇的构象空间,确定分子的最稳定构象之后,在DFT/B3LYP/6-31+G(d,p)水平上分别计算顺式和反式白藜芦醇上3个不同羟基形成自由基后的结构,从分子轨道,离解能,自由基的单电子分布、总自旋分布几个方面确定最有可能的反应中心,最后,解释化合物中的C=C对生物活性的影响。用类似的方法处理柚皮素与洋芹素,得到了二者的势能曲线,提取出其稳定结构,并通过计算推导出两个分子可能的抗氧化、消除自由基的活性中心。 第二部分:首先在DFT/B3LYP/6-31G(d)水平上对膜材料分子丙腈和甲基丙酸进行构象搜索,然后分别根据设想出的尿嘧啶和茶碱分子与膜材料的作用模型,用各个分子的稳定构象建模,并将所有模型在DFT/B3LYP/6-31+G(d,p)水平上进行结构优化和频率分析,并计算出经过零点能(ZPE)和基函数重叠误差(BSSE)校正的结合能。通过分别比较尿嘧啶与茶碱分子单体与复合物中的分子几何构型,振动光谱的变化,综合光谱比对和结合能大小两方面,得出分子与膜相互作用的可能机理。 第三部分:首先选取15种对表皮生长因子受体酪氨酸激酶(EGFR:1M17)有抑制活性的化合物,选择不同的方法对小分子进行构象分析,将所选取的这组分子的构象组合,利用Cerius2软件中的Ligandfit模块进行分子对接,比较每个分子的结合模式和活性的关系,总结抑制剂与蛋白质作用的规律。为了研究糖苷酶抑制剂——氨基糖对糖苷酶(AGLA:10BB)的抑制作用,本文阐述了α糖苷酶水解糖苷键的可能机理,并预测了两种可能的氨基糖与糖苷酶的结合模式。更多还原

【Abstract】 There are three parts in this paper: the first part is to make use of density functional theory to study the structure and electronic properties of the resveratrol, naringenin and apigenin molecules and to explain their antioxidant activities which are extracted from the Chinese traditional medicines; the second part is to research the mechanism of uracil molecular recognition membrane and theophyline molecular recognition membrane by using density functional theory too; the third part is to investigate the binding modes between the Epidermal growth factor receptor(EGFR) and its inhibitors, and the binding modes between the α -Glucosidase(AglA) and its amino-sugar inhibitor.The first part: The density function theory (DFT) is applied to study the conformations of trans-resveratrol and cis-resveratrol. Based on calculation results, in terms of the energy of abstracting H atom from hydroxybenzene, HOMO and LUMO, total spin density and unpaired electron distribution of resveratrols and their free radicals, we get to know the main active part of cis-resveratrol in scavenging free radicals is C4’-hydroxyl group too, the same with trans-resveratrol. The double bond between Cα and Cβ in the molecule plays an important role in their activity from comparison between trans-resveratrol, cis-resveratrol and α,β-dihydro-3,5,4’-trihydroxystilbene. The similar study is done to naringenin and apigenin molecules. Their steady structures are obtained and activity center are affirmed by computation and deduction.The second part: The interaction mechanism between uracil and its molecularly imprinted membrane, which is composed of acrylonitrile and methylacrylic acid, has been investigated by DFT method. Four possible complexes that there are hydrogen bonds between uracil and the membrane molecules are considered and their complete geometry optimizations are performed. A normal-mode analysis of the vibrations of the four complexes was carried out and compared with the experimental values. At last, the primary form of interaction is concluded based on the binding energy and vibrational spectrum. The similar study is done to the interaction of theophyline and its molecularly imprinted membrane.The third part: A series of various reported EGFR inhibitors are selected. Theconformation searches are performed to these inhibitors and the different methods of conformation searches such as systematise search, molecular dynamics and boltzman jump method, are adopted for different molecule based on their structure. The lower energy and varied conformations are combined to one sd file, then the docking between the Epidermal growth factor receptor (EGFR: 1M17) and inhibitors are performed by using the Ligandfit in the Cerius2, and then the docking modes are analyzed. The rule of this kind docking is induced. The similar study is done to investigate the docking modes between a -Glycosidase(10BB), and two different new docking modes are obtained.更多还原