基于受体结构的神经氨酸酶抑制剂的设计合成及生物活性研究
发布时间：2018-07-17 07:08
【摘要】：流感是一种呼吸道疾病,其致病机制为病毒的感染。现已经成为人类的健康主要杀手,每年世界范围内被感染的人群约总人口的千分之一。目前,预防和治疗流感病毒手段不多,主要防治方法为使用NAIs。然而随着越来越多耐药性病毒的出现,人类的健康时刻都面临着重大的威胁,因此开发新型的NAIs成为科学家面临越来越迫切的任务。 近些年来,科学家成功分离出药物小分子与NA受体蛋白的共结晶结构,并阐述了药物中各个药效基团与靶标蛋白中氨基酸残基的的作用方式,为设计和寻找新型NA抑制剂提供重要理论指导。目前上市的NAIs主要有zanamivir, oseltamivir和peramivir,其中oseltamivir因其良好的口服生物利用度而被广泛应用。然而随着药物的大量使用,使得耐oseltamivir病毒流行越来越广泛。其中某些特定的氨基酸(His274变异为Try274)变异所产生的新的病毒几乎对oseltamivir完全耐药。通过对NA蛋白质结构的深入研究,发现其存在两组亚型的结构,group-1结构包括N1、N4、N5、N8四种NA,group-2则包括N2、N3、N6、N7、 N9五种NA。比较group-1和group-2NA结构发现两者存在的显著的差异,在group-1NA结构的活性位点边缘存在一个大的活性空腔称为150-cavity。在通常情况下,group-1NA能够在配体分子的诱导下转变成group-2NA结构,因此目前的NAIs对group-1和group-2NA均有效,但当group-1NA中某些氨基酸如His274变异为Try274会使得group-1NA蛋白质结构失去转化为group-2NA结构的能力,就会表现出明显的耐药性。因此,基于上述的研究事实,我们尝试对oseltamivir的结构进行改造,前述的文献调研可知,oseltamivir的C-5位氨基指向疏水性的150-cavity,故本课题尝试在oseltamivir的C-5位氨基引入疏水基团,使之能够与150-cavity有作用力,从而制备高效,高选择性的NA抑制剂。通过对受体蛋白与配体作用方式的研究表明其NAIs的抑制活性与药效基团有关与载体无关,因此我们设计,合成了两类新型结构的NAIs具体的具体内容分为四个部分： (I).主要是介绍流感病毒的危害,NAIs重要性以及配体分子与蛋白的作用机制。NAIs的分类以及目前上市的三个药物的研究过程。最后提出本论文的设计思路。 (II).通过受体蛋白与配体作用方式的研究表明：oseltamivir的C-5氨基朝向150-cavity,从而为设计新型group-1NAIs提供新的思路。因此本课题拟以莽草酸为起始原料通过多步反应制备了20个oseltamivir C-5位疏水化改造的衍生物,其结构通过通过表征得到得以确认。活性测试显示该类结构的小分子group-1NA(H5N1)和group-2NA (H3N2)抑制活性。同时Autodock软件模拟验证了产物C-5位疏水基团与150-cavity存在相互作用,证明设计的合理性。 (Ⅲ)目前上市的药物小分子zanamivir,oseltamivir和peramivir等其结构中均存在手性中心,给其合成带来一定的困难。前述研究表明药效团的载体对NAIs的抑制活性的影响较小。故本课题拟用易制备的的苯环取代柔性的五元或者六元脂肪环,制备25个含苯环的NAIs。所得化合物的分子结构均通过表征得到确认,活性结果显示化合物III-39有中等的NA抑制活性(IC50=2.64μM)。通过分子模拟得到化合物与NA之间的相互作用关系。 (IV)通过受体蛋白与配体小分子的作用机制可知,NAIs对NA的抑制活性与配体的药效基团有关与载体并无直接关系。本课题设计合成了18个1,4,5,6-四氢嘧啶酮酸酯类小分子NAIs。其结构均得到有效验证,活性结果表明大部分制备的化合物有一定的NA抑制活性,其中化合物Ⅳ-33活性较好为(IC50=17.64μM)。通过分子模拟该类化合物与NA作用方式,发现其与上市药物oseltamivir与受体蛋白的作用相似。 综上所述,我们设计合成了三类不同结构的NAIs,同时测试其体外的NA抑制活性,并研究其与受体蛋白的作用机制,从而为进一步寻找结构新颖,高活性的NAIs提供重要的参考。
[Abstract]:Influenza is a respiratory disease , the pathogenic mechanism of which is the infection of the virus . Now it has become the main killer of human health . It is one tenth of the total population of people infected in the world every year . At present , there are not many methods to prevent and treat influenza virus . The main control method is to use NAIs . However , with the emergence of more and more drug - resistant viruses , human health is faced with a major threat , so the development of new NAIs has become a more and more pressing task for scientists .
In recent years , scientists have successfully isolated the co - crystalline structure of drug small molecule and NA receptor protein .
( I ) This paper mainly introduces the harm of influenza virus , the importance of NAIs and the mechanism of action of ligand molecule and protein . The classification of NAIs and the research process of three drugs currently marketed . Finally , the design idea of this paper is put forward .
In this study , 20 oseltamivir C - 5 hydrophobic modified derivatives were prepared by multi - step reaction with shikimic acid as the starting material , and the structure was confirmed by characterization . The activity test showed that the small molecule group - 1NA ( H5N1 ) and group - 2NA ( H3N2 ) inhibit the activity of the structure .
( 鈪，
本文编号：2129535
[Abstract]:Influenza is a respiratory disease , the pathogenic mechanism of which is the infection of the virus . Now it has become the main killer of human health . It is one tenth of the total population of people infected in the world every year . At present , there are not many methods to prevent and treat influenza virus . The main control method is to use NAIs . However , with the emergence of more and more drug - resistant viruses , human health is faced with a major threat , so the development of new NAIs has become a more and more pressing task for scientists .
In recent years , scientists have successfully isolated the co - crystalline structure of drug small molecule and NA receptor protein .
( I ) This paper mainly introduces the harm of influenza virus , the importance of NAIs and the mechanism of action of ligand molecule and protein . The classification of NAIs and the research process of three drugs currently marketed . Finally , the design idea of this paper is put forward .
In this study , 20 oseltamivir C - 5 hydrophobic modified derivatives were prepared by multi - step reaction with shikimic acid as the starting material , and the structure was confirmed by characterization . The activity test showed that the small molecule group - 1NA ( H5N1 ) and group - 2NA ( H3N2 ) inhibit the activity of the structure .
( 鈪，
本文编号：2129535
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