用于微创手术的止血药物新型缓释载体的开发及其分子模拟研究

发布时间：2018-04-10 03:02

本文选题：止血　切入点：光聚合　出处：《广州医科大学》2017年硕士论文

【摘要】：随着量子化学方法的逐渐发展,涌现了许多关于分子相互作用的研究。然而,这些研究多集中于静态聚集体如苯二聚体等,却很少研究反应过程中的动态变化,例如有机反应。变形能/相互作用能模型因其容易获得相互作用的能量值而非常适合用于研究反应过程中的动态变化。本论文在第一章利用MP2半经验方法来研究四个经典的双分子亲核取代反应(S_N2)中相互作用能(E_i)的变化,并同时研究了活化能(E_a)和变形能(E_d)的变化。S_N2反应因其在反应过程中会发生构型翻转,能量消耗较大而被选用于我们的研究中。能量和构象变化的分析表明,反应CH_3Br+OH~-的E_a和E_d最小。对于S_N2反应,反应发生的难易程度取决于亲核离子的亲核性,而我们发现E_a和E_d也类似地随着亲核性顺序改变。更有趣的发现是,E_i在过渡态(TS)时是负值,即E_i会降低反应势能垒。弱相互作用的研究表明,四个S_N2反应中均有弱相互作用,并且能够通过使用等值面图直观的“可视化”反应体系中的相互作用。与此同时,将E_i分解为四种能量后发现,交换能、重组能和静电能能够减少E_i,而动能增加E_i。键级、成键和断键指数的分析表明,反应CH_3Br+OH~-的TS出现早,即可以更早的形成反应复合物,导致其E_a较小。最后通过反应速率常数和隧穿因子的分析,反应CH_3Br+OH~-具有最大的反应速率常数。通过这些分析能让我们对四个反应的动态变化有更深入的了解,同时也能借助于相互作用能量来提供减少反应能量势垒的线索。产后低渗出血或子宫长期持续异常出血通常是由外源性损伤和内部疾病引起的,如凝血病和宫缩无力等。通过微创手术减少及治愈上述内部出血将是一种新趋势。在第二章我们利用多官能团可聚合蔗糖单体作为止血药持续释放的载体用于微创手术中治疗长期腔道内出血。本方法利用光聚合解决了在微通道输送中所遇到的流动性和粘附性的困境。紫外光解实验表明,三种含氨基结构的光惰性抗纤维蛋白溶解药和一种准光惰性药物可以作为载体药物。药物的光惰性还可以通过激发态计算得到的重组能来加以说明。使用实时红外实验以获得蔗糖单体的光聚合动力学,表明该配方通过光聚合可以快速完成,满足临床上快速成型的要求。粘度实验表明,本蔗糖单体具有剪切变稀的特性可以通过加压使其提高在微通道运输的流动性。体外药物释放实验和动物组织止血实验均证实了光聚合后的交联体不仅可以作为药物载体附着在出血点附近,还可以缓释出止血药发挥长期止血的功效。最后细胞毒性实验表明,单体及引发剂的细胞毒性良好。为了更深入地对止血机理进行研究,在第三章我们利用分子对接和分子动力学研究了四种止血药作为配体和人纤溶酶原kringle 1作为靶标的结合机制。通过分子对接获得四种药物与靶标的结合位点及其结合的方式,表明疏水作用在四个对接复合物中都扮演着重要的角色。分子动力学计算的结果表明,四个对接复合体中,复合物二乙酰氨乙酸乙二胺在模拟过程中经过较大的波动才达到平衡。结合自由能的计算结果表明,氨甲苯酸与靶标具有与最强的结合能力,而6-氨基己酸最弱。结合体外药物释放的结果,氨甲环酸具有较高的释放量且与靶标的结合能也较大,因此推荐其作为最合适的微创止血药。
[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.

【学位授予单位】：广州医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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