肽体药物分子设计的结构生物信息学研究

发布时间：2018-06-26 12:47

本文选题：多肽药物 + 肽体　；参考：《电子科技大学》2017年硕士论文

【摘要】：多肽在人体代谢的各个过程都承担了重要作用,其中包括细胞增殖、细胞分化、消化代谢、免疫防御、肿瘤病变等。在1953年,美国生化学家第一次人工合成了催产素这一多肽,标志着多肽可以为人们所利用。在经历了长期发展之后,现在在全球范围内上市的多肽药物已经超过了 80种,并且还有很多多肽药物处于正在研究的阶段。与其它药物相比,多肽类药物具有一些独特的优势:药效好,特异性高,通常在人体内不会产生累积,很少和其他药物发生交叉作用。多肽药物虽然具有上述的这些优势,不过同其它的药物对比,多肽药物同样存在着缺点:多肽的稳定性较低,常常被肽酶分解为氨基酸,这导致多肽的半衰期很短,为了保证药效需要重复为患者给药,很不方便。为解决这一问题,学者们探索了很多新方法,蛋白融合技术是目前延长蛋白和多肽类药物半衰期的有效手段之一。Fc融合则是目前研究最多、进展最快的蛋白融合技术,它通常是将IgG蛋白的Fc段同筛选出的多肽融合在一起。这样的多肽(Peptide)-抗体(Antibody)融合蛋白被称为“肽体”(Peptibody)。研究者发现:在罗米司亭(romiplostim)这一药物中,Fc段和多肽通过不同的方式连接所得到的活性差别极大。通过Fc的C端和多肽连接的活性相比于通过Fc的N端同多肽连接要高出10倍以上。但对多肽与抗体连接方式与药效间的关系和相应的机制还尚不清楚,对其的研究也更多集中在实验方面,理论上的探索寥寥无几。本学位论文拟从结构生物信息学角度出发,利用ITASSER在线服务预测蛋白结构以及ZDOCK对接蛋白从而构建相关的模型,预测分析出不同连接方式的肽体同受体的结合情况。然后通过AMBER等分子动力学模拟软件计算结合自由能以及能量分解的方法研究不同结合方式的肽体同受体的相互作用,从理论上尝试解释不同肽体药物连接方式不同所致的活性不同提供理论支持。也为以后设计肽体药物给出理论上的预测。
[Abstract]:Polypeptides play an important role in various processes of human metabolism, including cell proliferation, cell differentiation, digestion and metabolism, immune defense, tumor lesions, and so on. In 1953, American biochemists synthesized oxytocin for the first time, indicating that it could be used. After a long period of development, there are more than 80 polypeptide drugs on the market worldwide, and many polypeptide drugs are still in the research stage. Compared with other drugs, polypeptide drugs have some unique advantages: good efficacy, high specificity, usually do not accumulate in the human body, and rarely cross with other drugs. Although polypeptide drugs have these advantages, compared with other drugs, polypeptide drugs have the same disadvantages: the stability of peptides is low and they are often decomposed into amino acids by peptidases, which results in short half-lives of peptides. In order to ensure the efficacy of drugs need to be repeated for patients, very inconvenient. In order to solve this problem, many new methods have been explored. Protein fusion technology is one of the effective means to prolong the half-life of protein and polypeptide drugs. FC fusion is the most studied and the most advanced protein fusion technology. It usually fuses FC of IgG protein with selected peptides. This (Antibody) fusion protein is known as the Peptide body. The researchers found that in romistin (romiplostim), the activity of the FC segment and the peptide is significantly different from the way in which the peptide is connected. The binding activity of the C terminal of FC to the peptide was 10 times higher than that of the N terminal of FC. However, the relationship between peptide and antibody binding mode and pharmacokinetic activity and the corresponding mechanism are still unclear. The research on peptide and antibody is more focused on the experiment, and the theoretical research is very few. From the point of view of structural bioinformatics, this dissertation intends to use ITASSER online service to predict protein structure and ZDOCK docking protein to construct relevant models, and to predict and analyze the binding of peptide bodies with different binding modes to receptors. Then the binding free energy and energy decomposition were calculated by molecular dynamics simulation software, such as Amber, to study the interaction between peptide and receptor in different binding modes. This paper tries to explain the different activities caused by different peptide drug binding modes theoretically to provide theoretical support. It also provides a theoretical prediction for the design of peptide drugs in the future.
【学位授予单位】：电子科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R91

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