新德里金属-β-内酰胺酶-1抑制剂的虚拟筛选
发布时间：2018-10-26 19:37
【摘要】：产新德里金属-β-内酰胺酶-1(NDM-1)的“超级细菌”受到了全世界的广泛关注,它的质粒基因blaNDM-1能够在细菌间快速传播,产物NDM-1能够水解除氨曲南外的所有β-内酰胺类抗生素,整合了NDM-1的“超级细菌”对几乎所有的抗生素都有耐药性,它的出现正严重威胁着人类健康。筛选有效的NDM-1抑制剂以辅助现有β-内酰胺类抗生素的治疗是目前抗菌药物的研究热点,但至今还没有一个NDM-1抑制剂作为药物上市,所以发现新骨架、高活性、低毒性的NDM-1抑制剂具有重要意义。本文在构建NDM-1抑制剂药效团模型的基础上,建立了NDM-1抑制剂的筛选流程,利用分子动力学方法分析了潜在活性化合物的作用方式。首先,对35个NDM-1晶体结构进行了统计分析,发现了两种受体-配体的结合模式:模式A中,与Zn2+配位的配体基团有两个,并与两个Zn2+呈四边形结构,两个锌离子间还有一个水分子,也能够与其形成配位键;模式B中,与Zn2+配位的配体基团只有一个,并占据了模式A中水分子的位置,且与两个Zn2+呈三角形结构。随后本文根据这两种结合模式分别构建了两类药效团模型——药效团模型A和药效团模型B。其次,构建了一个逐层筛选方案并对Specs、Enamine、ChemDiv三大数据库共2857595个分子进行了虚拟筛选。第一步使用构建好的两个药效团筛选,共获得1409485个分子;第二步使用Surflex-Dock、MOEdock、AutoDock和Gold四种对接方法进行组合筛选,共获得4998个分子;第三步通过目筛保留了51个具有潜在活性的分子。最后,我们利用分子动力学模拟了51个潜在活性分子和NDM-1的相互作用。分析发现:1)活性位点锌离子的配位作用和静电作用对复合物结合发挥着关键作用,氢键和π-π共轭作用发挥着辅助作用。2)配体的电荷为-1时最有利于其结合NDM-1。3)结合模式A中配体基团与Zn1(与3个组氨酸配位)之间的作用方式根据距离可分为:配位作用,强静电作用和弱静电作用。本论文的研究对于解释NDM-1抑制剂作用机理,发现NDM-1抑制剂的新骨架具有指导意义。
[Abstract]:New Delhi metal- 尾 -lactamase-1 (NDM-1)-producing "super bacteria" have attracted worldwide attention. Its plasmid gene blaNDM-1 can spread rapidly among bacteria. The product NDM-1 can remove all 尾-lactam antibiotics outside of aztreonam in water, and the "super bacteria" that integrate NDM-1 are resistant to almost all antibiotics. Its emergence is a serious threat to human health. Screening effective NDM-1 inhibitors to assist the treatment of existing 尾 -lactam antibiotics is a hot topic in the research of antimicrobial agents at present. However, there is not a single NDM-1 inhibitor on the market as a drug so far, so the new skeleton and high activity have been found. Low toxicity NDM-1 inhibitors are of great significance. Based on the model of NDM-1 inhibitor pharmacophore, the screening process of NDM-1 inhibitor was established, and the action mode of potential active compound was analyzed by molecular dynamics method. First of all, 35 NDM-1 crystal structures were statistically analyzed and two receptor-ligand binding patterns were found: in mode A, there are two ligand groups coordinated with Zn2 and two Zn2 with quadrilateral structure. There is also a water molecule between the two zinc ions, with which a coordination bond can also be formed. In mode B, there is only one ligand group coordinated with Zn2, which occupies the position of water molecule in mode A and has a triangular structure with two Zn2. Then, two kinds of pharmacophore models, pharmacophore model A and pharmacophore model B, were constructed according to the two combined models. Secondly, a hierarchical screening scheme was constructed and a total of 2857595 molecules were selected from three databases of Specs,Enamine,ChemDiv. In the first step, a total of 1409485 molecules were obtained by screening with two pharmacophore groups constructed, and in the second step, a total of 4998 molecules were obtained by combined screening with four docking methods of Surflex-Dock,MOEdock,AutoDock and Gold. In the third step, 51 potentially active molecules were retained through the sieve. Finally, we use molecular dynamics to simulate the interaction of 51 potentially active molecules with NDM-1. It is found that: 1) the coordination and electrostatic interaction of zinc ions at active sites play a key role in the binding of the complexes. Hydrogen bond and 蟺-蟺 conjugation act as auxiliaries. 2) Ligand charge of -1 is most favorable for binding to NDM-1.3) the interaction between ligand group and Zn1 (coordination with three histidine) in mode A According to the distance, the formula can be divided into: coordination action, Strong electrostatic action and weak electrostatic action. The research in this paper is helpful to explain the mechanism of NDM-1 inhibitor and find the new skeleton of NDM-1 inhibitor.
【学位授予单位】：华中农业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R915
[Abstract]:New Delhi metal- 尾 -lactamase-1 (NDM-1)-producing "super bacteria" have attracted worldwide attention. Its plasmid gene blaNDM-1 can spread rapidly among bacteria. The product NDM-1 can remove all 尾-lactam antibiotics outside of aztreonam in water, and the "super bacteria" that integrate NDM-1 are resistant to almost all antibiotics. Its emergence is a serious threat to human health. Screening effective NDM-1 inhibitors to assist the treatment of existing 尾 -lactam antibiotics is a hot topic in the research of antimicrobial agents at present. However, there is not a single NDM-1 inhibitor on the market as a drug so far, so the new skeleton and high activity have been found. Low toxicity NDM-1 inhibitors are of great significance. Based on the model of NDM-1 inhibitor pharmacophore, the screening process of NDM-1 inhibitor was established, and the action mode of potential active compound was analyzed by molecular dynamics method. First of all, 35 NDM-1 crystal structures were statistically analyzed and two receptor-ligand binding patterns were found: in mode A, there are two ligand groups coordinated with Zn2 and two Zn2 with quadrilateral structure. There is also a water molecule between the two zinc ions, with which a coordination bond can also be formed. In mode B, there is only one ligand group coordinated with Zn2, which occupies the position of water molecule in mode A and has a triangular structure with two Zn2. Then, two kinds of pharmacophore models, pharmacophore model A and pharmacophore model B, were constructed according to the two combined models. Secondly, a hierarchical screening scheme was constructed and a total of 2857595 molecules were selected from three databases of Specs,Enamine,ChemDiv. In the first step, a total of 1409485 molecules were obtained by screening with two pharmacophore groups constructed, and in the second step, a total of 4998 molecules were obtained by combined screening with four docking methods of Surflex-Dock,MOEdock,AutoDock and Gold. In the third step, 51 potentially active molecules were retained through the sieve. Finally, we use molecular dynamics to simulate the interaction of 51 potentially active molecules with NDM-1. It is found that: 1) the coordination and electrostatic interaction of zinc ions at active sites play a key role in the binding of the complexes. Hydrogen bond and 蟺-蟺 conjugation act as auxiliaries. 2) Ligand charge of -1 is most favorable for binding to NDM-1.3) the interaction between ligand group and Zn1 (coordination with three histidine) in mode A According to the distance, the formula can be divided into: coordination action, Strong electrostatic action and weak electrostatic action. The research in this paper is helpful to explain the mechanism of NDM-1 inhibitor and find the new skeleton of NDM-1 inhibitor.
【学位授予单位】：华中农业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R915
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