新德里金屬-β-內(nèi)酰胺酶-1抑制劑的虛擬篩選
發(fā)布時間：2018-10-26 19:37
【摘要】：產(chǎn)新德里金屬-β-內(nèi)酰胺酶-1(NDM-1)的“超級細(xì)菌”受到了全世界的廣泛關(guān)注,它的質(zhì)�；騜laNDM-1能夠在細(xì)菌間快速傳播,產(chǎn)物NDM-1能夠水解除氨曲南外的所有β-內(nèi)酰胺類抗生素,整合了NDM-1的“超級細(xì)菌”對幾乎所有的抗生素都有耐藥性,它的出現(xiàn)正嚴(yán)重威脅著人類健康。篩選有效的NDM-1抑制劑以輔助現(xiàn)有β-內(nèi)酰胺類抗生素的治療是目前抗菌藥物的研究熱點(diǎn),但至今還沒有一個NDM-1抑制劑作為藥物上市,所以發(fā)現(xiàn)新骨架、高活性、低毒性的NDM-1抑制劑具有重要意義。本文在構(gòu)建NDM-1抑制劑藥效團(tuán)模型的基礎(chǔ)上,建立了NDM-1抑制劑的篩選流程,利用分子動力學(xué)方法分析了潛在活性化合物的作用方式。首先,對35個NDM-1晶體結(jié)構(gòu)進(jìn)行了統(tǒng)計(jì)分析,發(fā)現(xiàn)了兩種受體-配體的結(jié)合模式:模式A中,與Zn2+配位的配體基團(tuán)有兩個,并與兩個Zn2+呈四邊形結(jié)構(gòu),兩個鋅離子間還有一個水分子,也能夠與其形成配位鍵;模式B中,與Zn2+配位的配體基團(tuán)只有一個,并占據(jù)了模式A中水分子的位置,且與兩個Zn2+呈三角形結(jié)構(gòu)。隨后本文根據(jù)這兩種結(jié)合模式分別構(gòu)建了兩類藥效團(tuán)模型——藥效團(tuán)模型A和藥效團(tuán)模型B。其次,構(gòu)建了一個逐層篩選方案并對Specs、Enamine、ChemDiv三大數(shù)據(jù)庫共2857595個分子進(jìn)行了虛擬篩選。第一步使用構(gòu)建好的兩個藥效團(tuán)篩選,共獲得1409485個分子;第二步使用Surflex-Dock、MOEdock、AutoDock和Gold四種對接方法進(jìn)行組合篩選,共獲得4998個分子;第三步通過目篩保留了51個具有潛在活性的分子。最后,我們利用分子動力學(xué)模擬了51個潛在活性分子和NDM-1的相互作用。分析發(fā)現(xiàn):1)活性位點(diǎn)鋅離子的配位作用和靜電作用對復(fù)合物結(jié)合發(fā)揮著關(guān)鍵作用,氫鍵和π-π共軛作用發(fā)揮著輔助作用。2)配體的電荷為-1時最有利于其結(jié)合NDM-1。3)結(jié)合模式A中配體基團(tuán)與Zn1(與3個組氨酸配位)之間的作用方式根據(jù)距離可分為:配位作用,強(qiáng)靜電作用和弱靜電作用。本論文的研究對于解釋NDM-1抑制劑作用機(jī)理,發(fā)現(xiàn)NDM-1抑制劑的新骨架具有指導(dǎo)意義。
[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.
【學(xué)位授予單位】：華中農(nóng)業(yè)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：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.
【學(xué)位授予單位】：華中農(nóng)業(yè)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R915
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