發(fā)布時間：2018-02-27 14:17

  本文關(guān)鍵詞： 小牛胸腺DNA 血清白蛋白 索拉非尼 光譜法 分子模擬　出處：《浙江工業(yè)大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：本文通過使用包括紫外光譜、熒光光譜、圓二色光譜等多種光譜法與分子模擬法相互結(jié)合相互驗證的方式研究抗癌藥物索拉非尼與生物大分子相互作用,并利用分子模擬的方法對結(jié)合過程進行了微觀方面的解釋,本論文主要分為以下四個部分： 第一章,簡要介紹了生物大分子DNA及BSA的結(jié)構(gòu)和功能,綜述了抗癌藥物索拉非尼的研究進展,分析并解釋藥物小分子與生物大分子相互作用的方式,作用類型,結(jié)合位點以及各種光譜法和分子模擬法在實驗方面上的應(yīng)用進展,最后指出本實驗的研究意義。 第二章,使用紫外光譜、熒光競爭光譜、圓二色光譜法、粘度法、分子模擬法模擬人體環(huán)境下研究索拉非尼與小牛胸腺DNA(ct-DNA)的作用,實驗結(jié)果顯示索拉非尼與ct-DNA之間存在著相互作用。索拉非尼與ct-DNA在298K下的結(jié)合常數(shù)是5.6×103M-1,結(jié)合過程中的焓變和熵變分別為-27.66kJ mol-1,-21.02J mol-1K-1,表明結(jié)合過程中的主要作用力是范德華力和氫鍵力。分子對接的結(jié)果表明索拉非尼結(jié)合于ct-DNA的小溝區(qū),結(jié)合的區(qū)域是四個堿基對的長度。在對接的Sorafenib-DNA復(fù)合中,Sorafenib的結(jié)構(gòu)根據(jù)DNA構(gòu)象的不同而發(fā)生了明顯的改變,表明Sorafenib構(gòu)象的變化在結(jié)合的過程中起到了關(guān)鍵的作用。 第三章,采取熒光光譜法,圓二色光譜法與分子模擬法并用的方式在模擬人體環(huán)境下研究索拉非尼與牛血清白蛋白(BSA)的相互作用。實驗結(jié)果表明索拉非尼與BSA之間的相互作用是靜態(tài)猝滅,索拉非尼與BSA之間生成了復(fù)合物,且在310K時索拉非尼與BSA之間的結(jié)合常數(shù)是6.8×104L mo1-1,結(jié)合位點數(shù)是1。通過分析熱力學(xué)參數(shù)得到吉布斯自由能為負值,表明結(jié)合過程是自發(fā)的,結(jié)合過程中的焓變和熵變分別為-72.15kJ mol-1,-140.35J mol-1K-1,表明結(jié)合過程中的主要作用力是范德華力和氫鍵力,此實驗結(jié)果也通過分子模擬法證實。從熒光探針實驗得到索拉非尼結(jié)合于BSA的site Ⅰ區(qū)域,且BSA的二級結(jié)構(gòu)發(fā)生了輕微的改變,結(jié)合過程中為提高Sorafenib-BSA體系的穩(wěn)定性Sorafenib構(gòu)象也發(fā)生了變化。 第四章,對索拉非尼與大分子BSA、DNA的結(jié)合過程進行總結(jié),并展望未來可以進行的實驗方向。
[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，

本文編號：1543019