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一枝蒿酮酸衍生物虚拟筛选研究和天然产物结构解析平台建立
林健博
学位类型博士
导师阿吉艾克拜尔.艾萨
2012-06
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业有机化学
关键词一枝蒿酮酸 神经氨酸酶 虚拟筛选 结构解析平台 地锦草
摘要本论文前两章综述了流行性感冒(Influenza)简称流感对人类生命健康的危害,以及抗流感病毒的重要靶 标——神经氨酸酶。另外,我们完成了一枝蒿酮酸衍生物对神经氨酸酶N1, N2, N5, N8共四种亚型的虚拟筛选。 在所有亚型的甲型和乙型流感病毒表面分布的神经氨酸酶的催化中心的附近的一段11个氨基酸残基组成的序列高度保守,正是这一特点,使得流感病毒神经氨酸酶 成为抗流感病毒药物的一个很有意义的靶点。 我们以神经氨酸酶多种亚型三维结构为基础,对一枝蒿酮酸衍生物进行神经氨酸酶虚拟筛选,考察了一枝蒿酮酸母核各种取代基对活性的影响,并对活性化合物的机 理进行了解释,给出了今后结构修饰的建议。 第三章我们模建了神经氨酸酶N3蛋白的三维结构,并用于一支蒿酮酸衍生物的虚拟筛选。神经氨酸酶N3是一种糖苷外切酶,负责催化唾液酸与糖蛋白之间糖苷键 的水解,使成熟的病毒颗粒最终脱离宿主细胞,感染新的上皮细胞,造成流感病毒在患者体内的扩散。到目前为止,神经氨酸酶 N3 的三维结构还没有被人们所测定,但对其结构的了解对进行神经氨酸酶 N3 抑制剂的设计有重要意义。为此,我们采用同源模建的方法、以神经氨酸酶 N2 的晶体结构为模板构建了神经氨酸酶 N3 的三维结构模型,并运用理论计算方法和已有实验结果确定了神经氨酸酶 N3 的最佳模型。在此基础之上,我们运用动力学模拟的方法对神经氨酸酶 N3 与抗流感药物小分子的结合构象进行了研究。我们的神经氨酸酶 N3 模型为进行神经氨酸酶 N3 抑制剂的药物设计提供了结构基础。 第四章我们建立了天然产物波谱解析平台。在科学技术高度发达的今天,对于天然产物化学研究领域,分离得到的天然产物未知化合物的结构解析仍然是个难题,一 直以来都是依靠个人经验结合多种谱图进行综合解析。天然产物化合物种类繁多,结构复杂,在一些情况下,即使对于解谱经验非常丰富的专家,解析已知化合物的 难度,也不亚于解析新化合物。因此我们尝试发展一种高效的计算方法,用来对未知物波谱数据进行分析。目前,天然产物波谱数据解析平台已经完成了所有基本系 统模块的建设,为我们提供了一个非常方便的波谱解析工具,对已知化合物的解析是可靠的。用户除了输入核磁共振数据可以检索到与之相同或相近的化合物,还可 以通过分子式,原子量等多种方式进行检索,寻找可能的结构式。 第五章我们对地锦草抗菌和抗肿瘤活性成分进行研究。大戟属中的地锦草(Euphorbia humifusa Willd.)是一种一年生草本植物,分布于全国各地,尤以长江流域及南方各省为多,新疆各地都有分布。此植物普遍生长于平原荒地、路边、田间。它是一种 民间常用的中草药,其有效成分对多种微生物有抑制作用及抗痢疾作用。 地锦草作为传统药用植物,有着悠久的历史,虽然近些年用现代技术手段对它的活性成分进行了初步的研究,但这些研究的结果都只局限于单纯化学成分或生物活 性,与传统药用适应症相关的活性活性化合物或者活性机理一直没有突破。本文在此基础上验证了粗提物的抗肿瘤和抗微生物活性,测试了部分结构较新的化合物的 抗微生物活性。地锦草石油醚和氯仿部位表现出了有意义的Caco-2细胞抑制活性。虽然本论文没有找到地锦草生物活性的化合物,但通过确定5个本植物首次 分离的化合物,进一步明确了地锦草的化学成分,为进一步寻找先导化合物打下基础。我们同时测试了地锦草重要成分没食子酸(Gallic Acid)的抗微生物活性,发现化合物1和2的抑菌活性均好于没食子酸。事实上,由于这两种化合物只有微弱的抗微生物活性,因此要想寻找抗微生物的主要活 性成分,今后还需对地锦草进行更加深入的研究。
其他摘要The first two chapters reviewed the function and structure of neuraminidase and influenza virus which endanger the human being's health. And, virtual screening was performed on the neuraminidase N1, N2, N5, N8 subtypes with rupestonic acid derivatives. The structure of the active site is highly conserved among all nine influenza A neuraminidase subtypes and influenza B subtypes,that is the reason for neuraminidase to be a high-priority and promising target for anti-influenza agents. Based on the 3D structure of neuraminidase subtypes, we performed virtual screening on the rupestonic acid derivatives. A theoretical study of the influences of various substituents on the rupestonic acid derivatives, explained the mechanism of activity and gave advise for the future structure Modification. In the third chapter, we built a 3D model of neuraminidase N3 via homology modeling using the 3D structure of neuraminidase N2 as a template. This model can provide a structural basis for neuraminidase N3 inhibitor design. Then, the neuraminidase N3 and Zanamivir complexes was constructed by molecular docking based on our neuraminidase N3 model, which may facilitate studying the interactions between neuraminidase N3 and its ligands. Neuraminidase N3 is an exoglycosidase. It functions is catalyzing the cleavage of sialic acid residues from glycoprotein. It is thought to promote virus entry, and thereby enhances infection efficiency, and rationally designed NA inhibitors that prevent release of progeny virions away from infected cells are effective for the treatment of influenza. Thus, it serves as an important drug target. But the structure of neuraminidase N3 is not experimentally determined to date due to the technical difficulties. Finally, a potential activated/inactivated mechanism of neuraminidase N3 regulated was proposed based on the molecular dynamic simulation results, which may provide some useful information for drug design. The fourth chapter is about the platform of natural products spectrum analysis. In the modern chemical research of natural products, the structure analysis for isolated natural products is always a tough problem when science and technology were highly developed, and relying on personal experiences to comprehensive analysis the various spectra. The natural product compounds are rich in species numbers with complex structure; sometimes even the experts in spectrum analysis faced the difficulties with the known compounds as good as with the new ones. Therefore, we try to develop an efficient compute method to analysis the unknown compounds’ spectral data. Now, all the basic system modules of spectral data analysis platform for natural product compounds are established. It is a convenient spectrum analysis tool and its analysis about the known compounds is reliable. Users can find the same or similar compounds by search with NMR data. There are many ways to do the retrieval, such as molecular formula and atomic weight. In the last chapter, the antimicrobial and antitumor activities of crude extracts and isolated compounds from Euphorbia humifusawere tested. Euphorbia humifusa Willd is an annual herb, can be find all over china and especially much in the Yangtze River Basin and the southern provinces. It grows in plain, desolation land and roadside. It used in traditional Chinese medicine for the treatment of dysentery, enteritis, and hematochezia. Euphorbia humifusa Willd is a traditional medicine with long history. Recent years, preliminary study was done about its activity composition though modern technology. But these studies were limit in pure chemical constituents or biological activity. The research about activity compounds related with traditional medicinal indication or activity mechanism has no breakthrough. Based on this, antimicrobial and antitumor activities of crude extracts were verified in this chapter. The antimicrobial activities of compounds 1-2 were evaluated. Petroleum ether and chloroform fractions significantly exhibit potent antigrowth activity against Caco-2 cells. The promising bioactivities of the crude petroleum ether fractions guided the first isolation of 5 compounds, and we further make clear chemical constituents of Euphorbia humifusa as a basis for further study, but we didn't get active compounds from Euphorbia humifusa. Meanwhile, the antimicrobial activity of gallic acid was tested. The antimicrobial activities of compounds 1-2 were better than gallic acid. In fact, it showed moderate growth inhibition against Staphyloccocus aureus. In order to find high active compounds with antimicrobial and antitumor properties, this plant should be further researched for microbial infections and cancer.
文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/4366
专题资源化学研究室
作者单位中国科学院新疆理化技术研究所
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林健博. 一枝蒿酮酸衍生物虚拟筛选研究和天然产物结构解析平台建立[D]. 北京. 中国科学院研究生院,2012.
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