人类核糖核苷酸还原酶的模拟分子对接

发布时间：2018-06-04 15:35

本文选题：核糖核苷酸还原酶 + 虚拟筛选　；参考：《浙江大学》2012年硕士论文

【摘要】：核糖核苷酸还原酶(RR)是人类体内唯一的催化4种核糖核苷酸还原、生成相应的脱氧核糖核苷酸的酶。研究表明,人体小亚基R2能促进各种致癌基因的转变,提高癌细胞的入侵能力。因此通过,研究R2抑制剂,抑制肿瘤细胞的生成和转移,已成为治愈人类癌肿的靶点研究之一,越来越受到关注。本文从结构生物信息学的角度研究人体中RR的小亚基R2蛋白质。首先,我们应用metaPocket2.0找出R2表面上可能的小分子作用位点,应用AutoDock Vina蛋白质与小分子对接软件对ZINC、DrugBank和PDB数据库中大规模的小分子进行了虚拟筛选,筛选出9个可用于实验验证的小分子化合物。我们筛选出一个新的R2抑制剂,格列喹酮,它与2个活性位点的结合亲和力值最好,为下一步实验验证提供依据。接着,我们应用ZDOCK蛋白质-蛋白质对接软件进行R1和R2模拟对接,并利用metaPPI预测出R1和R2上的蛋白质结合位点,构造出4种RR全酶模型。最后,通过从结构和序列上比较人类R2与大肠杆菌的R2,以及通过KFC、FlodX、HOTPOINT和HotSpot Wizard4种软件预测,得到了R2二聚体结合表面上的1对热点氨基酸A_PHE101-D_PHE101,它们在氨基酸序列上和空间结构上都是完全对称的。本文的结果可为后续实验筛选作用于R2的小分子药物及研究R2二聚体形成机制提供可靠的理论依据,具有一定的参考意义。
[Abstract]:Ribonucleotide reductase (RR) is the only enzyme that catalyzes the reduction of 4 ribonucleotides in human body to produce the corresponding deoxyribonucleotide. The study shows that the small subunit R2 can promote the transformation of all kinds of oncogenic genes and improve the invasion ability of cancer cells. Therefore, the development of R2 inhibitors and the inhibition of the formation and metastasis of tumor cells have been developed. In order to cure human cancer target, more and more attention is paid. This paper studies the small subunit R2 protein of RR in human body from the perspective of structural bioinformatics. First, we use metaPocket2.0 to find the possible small molecular action loci on the surface of R2, and use the AutoDock Vina egg white and small molecule docking software for ZINC, DrugBank and PDB. In the database, a large number of small molecules were screened to screen 9 small molecular compounds that could be used for experimental verification. We screened a new R2 inhibitor, Glico - one, which has the best binding affinity with 2 active sites, and provides the basis for the next experimental verification. Then, we apply the ZDOCK protein protein docking. The software carries out R1 and R2 simulative docking, and uses metaPPI to predict protein binding sites on R1 and R2, and constructs 4 RR full enzyme models. Finally, by comparing the R2 of human R2 and Escherichia coli from the structure and sequence, and through the prediction of KFC, FlodX, HOTPOINT, and HotSpot, 1 pairs of heat on the surface of the two polymer are obtained. The amino acid A_PHE101-D_PHE101, both in the amino acid sequence and in the spatial structure, are completely symmetrical. The results of this paper can provide a reliable theoretical basis for the subsequent screening of small molecular drugs acting on R2 and the mechanism of the formation of R2 two polymer, which has some reference meaning.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R341

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