本文選題：止血　切入點：光聚合　出處：《廣州醫(yī)科大學(xué)》2017年碩士論文

【摘要】：隨著量子化學(xué)方法的逐漸發(fā)展,涌現(xiàn)了許多關(guān)于分子相互作用的研究。然而,這些研究多集中于靜態(tài)聚集體如苯二聚體等,卻很少研究反應(yīng)過程中的動態(tài)變化,例如有機反應(yīng)。變形能/相互作用能模型因其容易獲得相互作用的能量值而非常適合用于研究反應(yīng)過程中的動態(tài)變化。本論文在第一章利用MP2半經(jīng)驗方法來研究四個經(jīng)典的雙分子親核取代反應(yīng)(S_N2)中相互作用能(E_i)的變化,并同時研究了活化能(E_a)和變形能(E_d)的變化。S_N2反應(yīng)因其在反應(yīng)過程中會發(fā)生構(gòu)型翻轉(zhuǎn),能量消耗較大而被選用于我們的研究中。能量和構(gòu)象變化的分析表明,反應(yīng)CH_3Br+OH~-的E_a和E_d最小。對于S_N2反應(yīng),反應(yīng)發(fā)生的難易程度取決于親核離子的親核性,而我們發(fā)現(xiàn)E_a和E_d也類似地隨著親核性順序改變。更有趣的發(fā)現(xiàn)是,E_i在過渡態(tài)(TS)時是負(fù)值,即E_i會降低反應(yīng)勢能壘。弱相互作用的研究表明,四個S_N2反應(yīng)中均有弱相互作用,并且能夠通過使用等值面圖直觀的“可視化”反應(yīng)體系中的相互作用。與此同時,將E_i分解為四種能量后發(fā)現(xiàn),交換能、重組能和靜電能能夠減少E_i,而動能增加E_i。鍵級、成鍵和斷鍵指數(shù)的分析表明,反應(yīng)CH_3Br+OH~-的TS出現(xiàn)早,即可以更早的形成反應(yīng)復(fù)合物,導(dǎo)致其E_a較小。最后通過反應(yīng)速率常數(shù)和隧穿因子的分析,反應(yīng)CH_3Br+OH~-具有最大的反應(yīng)速率常數(shù)。通過這些分析能讓我們對四個反應(yīng)的動態(tài)變化有更深入的了解,同時也能借助于相互作用能量來提供減少反應(yīng)能量勢壘的線索。產(chǎn)后低滲出血或子宮長期持續(xù)異常出血通常是由外源性損傷和內(nèi)部疾病引起的,如凝血病和宮縮無力等。通過微創(chuàng)手術(shù)減少及治愈上述內(nèi)部出血將是一種新趨勢。在第二章我們利用多官能團可聚合蔗糖單體作為止血藥持續(xù)釋放的載體用于微創(chuàng)手術(shù)中治療長期腔道內(nèi)出血。本方法利用光聚合解決了在微通道輸送中所遇到的流動性和粘附性的困境。紫外光解實驗表明,三種含氨基結(jié)構(gòu)的光惰性抗纖維蛋白溶解藥和一種準(zhǔn)光惰性藥物可以作為載體藥物。藥物的光惰性還可以通過激發(fā)態(tài)計算得到的重組能來加以說明。使用實時紅外實驗以獲得蔗糖單體的光聚合動力學(xué),表明該配方通過光聚合可以快速完成,滿足臨床上快速成型的要求。粘度實驗表明,本蔗糖單體具有剪切變稀的特性可以通過加壓使其提高在微通道運輸?shù)牧鲃有�。體外藥物釋放實驗和動物組織止血實驗均證實了光聚合后的交聯(lián)體不僅可以作為藥物載體附著在出血點附近,還可以緩釋出止血藥發(fā)揮長期止血的功效。最后細胞毒性實驗表明,單體及引發(fā)劑的細胞毒性良好。為了更深入地對止血機理進行研究,在第三章我們利用分子對接和分子動力學(xué)研究了四種止血藥作為配體和人纖溶酶原kringle 1作為靶標(biāo)的結(jié)合機制。通過分子對接獲得四種藥物與靶標(biāo)的結(jié)合位點及其結(jié)合的方式,表明疏水作用在四個對接復(fù)合物中都扮演著重要的角色。分子動力學(xué)計算的結(jié)果表明,四個對接復(fù)合體中,復(fù)合物二乙酰氨乙酸乙二胺在模擬過程中經(jīng)過較大的波動才達到平衡。結(jié)合自由能的計算結(jié)果表明,氨甲苯酸與靶標(biāo)具有與最強的結(jié)合能力,而6-氨基己酸最弱。結(jié)合體外藥物釋放的結(jié)果,氨甲環(huán)酸具有較高的釋放量且與靶標(biāo)的結(jié)合能也較大,因此推薦其作為最合適的微創(chuàng)止血藥。
[Abstract]:With the gradual development of quantum chemical methods, there have been many studies about the molecular interaction. However, these studies focused on static aggregates such as benzene two dimers, but few studies on dynamic changes of the reaction process, such as organic reactions. The deformation energy / interaction energy model because of its easy access to the interaction energy the value is very suitable for the study on the dynamic change of the reaction process. The first chapter of this paper using MP2 semi empirical method to study the four classical bimolecular nucleophilic substitution reaction (S_N2) in the interaction energy (E_i) changes, and at the same time on the activation energy (E_a) and deformation (E_d) the change of.S_N2 due to the stereoinversion reaction in the reaction process, high energy consumption and was selected for our study. The analysis of energy and conformational changes show that the reaction of CH_3Br+OH~- E_a and E_d minimum. For the S_N2 reaction, reaction The degree of difficulty depends on nucleophilic ion nucleophiles, and we found that E_a and E_d are similar with the nucleophilic sequence change. More interesting is, E_i in the transition state (TS) when E_i is negative, which will decrease the reaction potential energy barrier. The research shows that the weak interaction, four a S_N2 reaction has weak interaction, and can use the isosurface diagram "visualization" in the reaction system interaction. At the same time, E_i is divided into four kinds, energy exchange, reorganization energy and electrostatic energy can reduce the E_i, and the kinetic energy of the E_i. bond order, bond and bond breaking index analysis showed that the reaction of CH_3Br+OH~- TS appeared earlier, that can form a complex reaction earlier, due to the smaller E_a. Finally through the analysis and reaction rate constants of tunnel wear factor, CH_3Br+OH~- has the maximum reaction rate constant of reaction. Through these analyses can make The dynamic changes of the four reactions have a more in-depth understanding, but also with the help of the interaction energy to provide clues. Reduce the reaction energy barrier for uterine bleeding or prolonged bleeding is usually caused by exogenous injury and internal diseases such as low permeability postpartum, blood coagulation disease and uterine atony by minimally invasive. The internal bleeding and reduce surgical cure will be a new trend. In the second chapter, we use the polyfunctional polymerizable monomer as carrier of sucrose hemostatic drug sustained release for long-term cavity hemorrhage minimally invasive surgical treatment. This method uses the photo polymerization to solve the mobility and adhesion encountered in micro channel transport the dilemma. Showed that the UV photolysis experiments, three kinds of light inert amino containing structure of antifibrinolytic drugs and a quasi optical inert drug can be used as carrier for drugs. The drug can also light inert Through the calculation of the reorganization energy excited state to be described. Using real-time infrared experiment to obtain sucrose monomer photo polymerization kinetics, show that the formula by photopolymerization can be completed quickly and meet the clinical requirements of rapid prototyping. The viscosity experiments showed that the sucrose monomer has shear thinning properties can be enhanced by pressure liquidity in the micro channel transport. The in vitro drug release experiments and animal tissue bleeding were confirmed after photo polymerization crosslinking body not only can be used as a drug carrier attached to the bleeding point, also can release out hemostatic drugs play a long-term hemostatic effect. That the final cell toxicity experiment, monomer and trigger cytotoxic agent is good in order to further study on the hemostatic mechanism in the third chapter, we use molecular docking and molecular dynamics study of the four kinds of hemostatic and fibrinolytic enzyme as ligand The original kringle 1 as the target binding mechanism. Through molecular docking for binding sites of four kinds of drugs and the target and its combination showed that hydrophobic interaction plays an important role in the four docking complex. Molecular dynamics calculation results show that the four docking complexes, complex two acetyl diaceturate in the simulation process through large fluctuations to reach equilibrium. Binding free energy calculation results show that aminomethylbenzoic acid and the target with the strongest binding capacity, while 6- aminocaproic acid was the weakest. Combined with in vitro drug release results, combined with the release of tranexamic acid is higher and the target can be larger, therefore recommended the most suitable as a minimally invasive hemostatic.

【學(xué)位授予單位】：廣州醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943

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