基于端粒G-四链体配体药效团模型的研究

发布时间：2018-02-27 10:12

本文关键词： 端粒酶 G-四链体配体药效团模型分子对接　出处：《中央民族大学》2016年硕士论文　论文类型：学位论文

【摘要】：G-四链体存在于人类很多重要部位,如癌基因启动子区域以及染色体末端的端粒。它是由富含鸟嘌呤(G Guanine)的DNA序列在某种环境条件下自身组装而成的特殊二级结构。在癌细胞以及永生化细胞系中,端粒酶显示活性,能够起到对端粒的延长作用,而G-四链体的存在抑制了端粒酶的活性,使细胞在分裂过程中端粒逐渐缩短,细胞正常走向灭亡。靶向G-四链体的抗癌药物设计成为了当前十分重要手段,因此本文构建了基于端粒G-四链体配体、受体、受体-配体复合物构建药效团模型,并利用含有活性和非活性的配体测试集进行药效团模型的验证。然后以三个药效团模型在天然产物数据库中进行高通量的虚拟筛选,先通过快速分子对接和半柔性对接,再通过半柔性的精准分子对接技术。在理论上确认了端粒G-四链体的配体化合物。本文主要研究内容和结果如下：分别基于端粒G-四链体配体、受体、受体-配体复合物构建了药效团模型,并利用含有活性和非活性的测试集对药效团模型进行验证,选择三个最佳的药效团模型。以三个最佳的药效团模型在天然产物数据库中进行高通量的虚拟筛选,得到3600个化合物,根据类药性原则和和Veber原则过滤掉一大部分化合物,三个模型分别剩下化合物377、359、362个化合物,这些剩下的化合物都具有成药的可能性。先对筛选结果进行快速分子对接技术,三个模型的化合物分别剩下270、208、256个。然后利用半柔性分子对接技术对以上三个模型所剩下的化合物中打分排名前50的化合物进行一致性打分评价,根据打分情况和三个模型共有的化合物进行分析,Cimiracemate B、Cimiracemate C、Cimiracemate D、Anticancer Stilbenolignan PM V70P691-042、Anticancer Flavonoid PMV70P691-97为最佳化合物。最终通过半柔性精准分子对接技术对以上五个化合物进行分子对接并分析对接结果。最终确认以上五个化合物在理论上可作为端粒G-四链体的配体,为抗癌药物的研发和设计提供了一定的理论基础。
[Abstract]:The G-quadruplex exists in many important parts of human beings. Such as the promoter region of the oncogene and the telomere at the end of the chromosome. It is a special secondary structure assembled by a DNA sequence rich in guanine under certain environmental conditions. In cancer cells and immortalized cell lines, Telomerase activity can prolong the telomere, and the existence of G-quad inhibits the telomerase activity, which makes the telomere shorten gradually during cell division. The design of anticancer drugs targeting G-quadruplex has become a very important means, so we have constructed a pharmacophore model based on telomeric G-quad ligand, receptor and receptor-ligand complex. The pharmacophore model was verified by using the ligands containing active and inactive ligands. Then three pharmacophore models were used to perform high-throughput virtual screening in the natural product database. First, rapid molecular docking and semi-flexible docking were performed. The ligand compounds of telomere G-quadruplex were theoretically confirmed by semi-flexible precise molecular docking technique. The main contents and results of this paper are as follows: based on telomere G-quad ligand, receptor, The pharmacophore model was constructed by receptor-ligand complex, and the pharmacophore model was verified by test set containing active and inactive. Three best pharmacophore models were selected. Three best pharmacophore models were used to carry out high-throughput virtual screening in the natural product database, and 3,600 compounds were obtained, and a large number of compounds were filtered out according to the drug-like and Veber principles. There are 377,359,362 compounds left in each of the three models, and the remaining compounds have the possibility of proprietary medicine. The screening results are first screened by rapid molecular docking. The compounds of the three models were 270, 208 and 256, respectively. Then the consistency of the top 50 compounds of the three models was evaluated by using the semi-flexible molecular docking technique. According to the scoring situation and the common compounds of the three models, the Cimiracemate Cimiracemate Cor Cimiracemate DU Anticancer Stilbenolignan PM V70P691-042Anticancer Flavonoid PMV70P691-97 was selected as the best compound. Finally, the molecular docking of the above five compounds was carried out by semi-flexible precise molecular docking technique. Finally confirmed that the above five compounds could theoretically be used as ligand of telomeric G-quadruplex, It provides a theoretical basis for the development and design of anticancer drugs.
【学位授予单位】：中央民族大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R91

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