索拉非尼与生物大分子相互作用的研究

发布时间：2018-02-27 14:17

  本文关键词： 小牛胸腺DNA 血清白蛋白 索拉非尼 光谱法 分子模拟　出处：《浙江工业大学》2014年硕士论文　论文类型：学位论文

【摘要】：本文通过使用包括紫外光谱、荧光光谱、圆二色光谱等多种光谱法与分子模拟法相互结合相互验证的方式研究抗癌药物索拉非尼与生物大分子相互作用,并利用分子模拟的方法对结合过程进行了微观方面的解释,本论文主要分为以下四个部分： 第一章,简要介绍了生物大分子DNA及BSA的结构和功能,综述了抗癌药物索拉非尼的研究进展,分析并解释药物小分子与生物大分子相互作用的方式,作用类型,结合位点以及各种光谱法和分子模拟法在实验方面上的应用进展,最后指出本实验的研究意义。 第二章,使用紫外光谱、荧光竞争光谱、圆二色光谱法、粘度法、分子模拟法模拟人体环境下研究索拉非尼与小牛胸腺DNA(ct-DNA)的作用,实验结果显示索拉非尼与ct-DNA之间存在着相互作用。索拉非尼与ct-DNA在298K下的结合常数是5.6×103M-1,结合过程中的焓变和熵变分别为-27.66kJ mol-1,-21.02J mol-1K-1,表明结合过程中的主要作用力是范德华力和氢键力。分子对接的结果表明索拉非尼结合于ct-DNA的小沟区,结合的区域是四个碱基对的长度。在对接的Sorafenib-DNA复合中,Sorafenib的结构根据DNA构象的不同而发生了明显的改变,表明Sorafenib构象的变化在结合的过程中起到了关键的作用。 第三章,采取荧光光谱法,圆二色光谱法与分子模拟法并用的方式在模拟人体环境下研究索拉非尼与牛血清白蛋白(BSA)的相互作用。实验结果表明索拉非尼与BSA之间的相互作用是静态猝灭,索拉非尼与BSA之间生成了复合物,且在310K时索拉非尼与BSA之间的结合常数是6.8×104L mo1-1,结合位点数是1。通过分析热力学参数得到吉布斯自由能为负值,表明结合过程是自发的,结合过程中的焓变和熵变分别为-72.15kJ mol-1,-140.35J mol-1K-1,表明结合过程中的主要作用力是范德华力和氢键力,此实验结果也通过分子模拟法证实。从荧光探针实验得到索拉非尼结合于BSA的site Ⅰ区域,且BSA的二级结构发生了轻微的改变,结合过程中为提高Sorafenib-BSA体系的稳定性Sorafenib构象也发生了变化。 第四章,对索拉非尼与大分子BSA、DNA的结合过程进行总结,并展望未来可以进行的实验方向。
[Abstract]:In this paper, the interaction of the anticancer drug Solafenib with biological macromolecules was studied by means of the combination of UV spectra, fluorescence spectra, circular dichroism spectroscopy and molecular simulation. The microcosmic explanation of the binding process is carried out by using the molecular simulation method. This paper is divided into the following four parts:. In the first chapter, the structure and function of DNA and BSA are briefly introduced, and the research progress of the anticancer drug Solafenib is reviewed, and the ways and types of interaction between small molecules and biomolecules are analyzed and explained. The application of binding sites and various spectral and molecular simulation methods in experiments is also discussed. Finally, the significance of this experiment is pointed out. In the second chapter, the effects of Solafenil and calf thymus DNA-ct-DNA were studied by ultraviolet spectrum, fluorescence competitive spectrum, circular dichroism spectroscopy, viscosity method and molecular simulation method. The experimental results show that there is an interaction between Solafenib and ct-DNA, the binding constant of Solafenib and ct-DNA is 5.6 脳 103M-1 at 298K, the enthalpy variation and entropy change in the binding process are -27.66 kJ mol-1 -21.02J mol-1 K-1K-1respectively, indicating that the main force in the binding process is normed. The results of molecular docking show that Solafenib binds to the small groove region of ct-DNA. The binding region is the length of four base pairs. The structure of Sorafenib is changed obviously according to the conformation of DNA, which indicates that the change of conformation of Sorafenib plays a key role in the binding process. Chapter three, fluorescence Spectrometry, The interaction between solafenib and bovine serum albumin (BSA) was studied by using circular dichroism and molecular simulation in simulated human environment. The experimental results show that the interaction between solafenib and BSA is static quenching. A complex was formed between Solafenib and BSA. At 310 K, the binding constant between Solafenib and BSA was 6.8 脳 104L mo1-1, and the binding site number was 1.The Gibbs free energy was negative by analyzing thermodynamic parameters, which indicated that the binding process was spontaneous. The enthalpy change and entropy change in the binding process are -72.15 kJ mol -1 + -140.35 J mol -1 K -1, respectively, indicating that the main forces in the binding process are van der Waals force and hydrogen bond force. The results were also confirmed by molecular simulation. Solafenil binding to the site 鈪，

本文编号：1543019