基于计算机虚拟筛选技术寻找NDM-1抑制剂
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摘要
β-内酰胺类抗生素的广泛使用,使得越来越多的细菌产生由β-内酰胺酶介导的耐药性,针对丝氨酸β-内酰胺酶,目前已有克拉维酸、舒巴坦等抑制剂与临床常用抗生素配伍使用,但尚无金属β-内酰胺酶的有效抑制剂,因此,寻找金属β-内酰胺酶尤其是目前最受瞩目的新德里金属β-内酰胺酶-1[NDM-1(B1类)]的抑制剂是遏制"超级细菌"引起的感染最迫切的要求。虚拟筛选作为发现新的先导化合物、寻找新药物的有力手段,大大缩小了人工进行配体活性筛选研究范围。我们通过计算机虚拟筛选技术,利用Discovery Studio 2.5和GOLD 3.0平台,基于NDM-1晶体结构(PDB:3Q6X),从一个含有2059个天然产物分子的化合物库里筛选得到6个可能具有金属β-内酰胺酶NDM-1(B1类)抑制活性的化合物结构。
The wide use of β-lactam antibiotics makes more and more bacteria produce β-lactamasemediated resistance. For serine β-lactamase, inhibitors like clavulanic acid, Sulbactam are used in clinical treatment, which are combined with commonly used antibiotics. But there is no effective inhibitor of metal β-lactamase. Therefore, the inhibitors searched for metal β-lactamase, especially the most watched NDM-1(B1 class) are the most pressing requirements to contain infections caused by ‘super bacteria' As a powerful tool to find new lead compounds and new drugs, the virtual screening greatly reduces the scope for artificial screening of ligand activity. We screened from a library of 2059 natural product molecules based on the NDM-1 crystal structure(PDB: 3 Q6 X) using computer-aided virtual screening via the Discovery Studio 2.5 and GOLD 3.0 platforms and get 6 compound structure which may have NDM-1(class B1) inhibiting activity.
The wide use of β-lactam antibiotics makes more and more bacteria produce β-lactamasemediated resistance. For serine β-lactamase, inhibitors like clavulanic acid, Sulbactam are used in clinical treatment, which are combined with commonly used antibiotics. But there is no effective inhibitor of metal β-lactamase. Therefore, the inhibitors searched for metal β-lactamase, especially the most watched NDM-1(B1 class) are the most pressing requirements to contain infections caused by ‘super bacteria' As a powerful tool to find new lead compounds and new drugs, the virtual screening greatly reduces the scope for artificial screening of ligand activity. We screened from a library of 2059 natural product molecules based on the NDM-1 crystal structure(PDB: 3 Q6 X) using computer-aided virtual screening via the Discovery Studio 2.5 and GOLD 3.0 platforms and get 6 compound structure which may have NDM-1(class B1) inhibiting activity.
引文
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[2]曾建涛,李泉.Ⅰ型新德里金属β内酰胺酶的生物信息学分析[J].中国生物制品学杂志,2011(11):1300-1302.
[3]Thomas Pei W,Zheng Min,Wu Shanshan,et al.Characterization of purified New Delhi metallo-betalactamase-1[J].Biochemistry,2011,50(46):10102-10113.
[4]King D,Strynadka N.Crystal structure of New Delhi metallo-beta-lactamase reveals molecular basis for antibiotic resistance[J].Pro Sci,2011,20(9):1484-1491.
[5]李兴华,肖春玲.NDM-1酶及其抑制剂研究进展[J].中国新药杂志,2016(03):270-276.
[6]Yong D,Toleman Mark A,Giske Christian G,et al.Characterization of a New metallo-beta-lactamase gene,bla(NDM-1),and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India[J].Antimicrob Agents Chemother,2009.53(12):5046-5054.
[7]王盛书,孙金柱,苏文莉,等.我国携带NDM-1基因耐药菌流行现况分析[J].军事医学,2015(11):825-830.
[8]Kitchen DB,Decornez H,Furr JR,et al.Docking and scoring in virtual screening for drug discovery:methods and applications[J].Nat Rev Drug Dis,2004,3(11):935-949.
[9]周丹丹,郑珩,顾觉奋.“超级细菌”NDM-1的研究进展[J].中国新药杂志,2013(16):1907-1911.
[10]陈辉,沈秉正,周亚丽,等.金属-内酰胺酶催化机制的研究进展[J].国外医药抗生素分册,2011(06):245-252.
[11]郑卫.β-内酰胺酶及其抑制剂研究进展[J].国外医药抗生素分册,2001(02):49-56.
[12]沈秉正,郑珩,倪孟祥.B型金属β-内酰胺酶抑制剂研究进展[J].中国新药杂志,2011(02):143-147.
[13]Wang X,Liu M,Shi Y,et al.Discovery of novel New Delhi metallo-beta-lactamases-1 inhibitors by multistep virtual screening[J].Plos One,2015,10(3):e0118290.
[14]Thakur PK,Kumar J,Ray D,et al.Search of potential inhibitor against New Delhi metallo-beta-lactamase 1 from a series of antibacterial natural compounds[J].J Nat Sci biol med,2013,4(1):51-56.
[15]Jones G,Willett P,Glen RC,et al.Development and validation of a genetic algorithm for flexible docking[J].J Mol Biol,1997,267(3):727-748.
[16]Warren GL,Andrew C,Capelli A,et al.A critical assessment of docking programs and scoring functions[J].J Med Chem,2006,49(20):5912-5931.
[17]顾觉奋,沙磊,金属β-内酰胺酶抑制剂研究新进展[J].抗感染药学,2010(02):73-77.
[18]陈照强,刘一方,朱宁,等.金属β-内酰胺酶的研究进展[J].国外医药抗生素分册,2011(03):111-115.
[19]谭艳红,张姝,冯连顺.潜在的金属β-内酰胺酶抑制剂的研究进展[J].国外医药抗生素分册,2014(02):63-68.
[20]King AM,Reid-Yu Sarah A,Wang Wenliang,et al.Aspergillomarasmine a overcomes metallo-beta-lactamase antibiotic resistance[J].Nature,2014,510(7506):503-506.