多靶点的抗菌先导化合物的虚拟筛选及活性研究

doi:10.11843/j.issn.0366-6964.2018.07.020

畜牧兽医学报 ›› 2018, Vol. 49 ›› Issue (7): 1500-1510.doi: 10.11843/j.issn.0366-6964.2018.07.020

多靶点的抗菌先导化合物的虚拟筛选及活性研究

蔡珺珺, 袁田青, 杨银萍, 高双, 宫兴文*

浙江工商大学食品与生物工程学院, 杭州 310018

收稿日期:2017-09-29 出版日期:2018-07-23 发布日期:2018-07-23
通讯作者: 宫兴文(1971-),男,副教授,黑龙江哈尔滨人,主要从事食品生物技术研究,E-mail:gongxingwen@163.com
作者简介:蔡珺珺(1993-),女,安徽广德人,硕士生,主要从事抗菌先导化合物筛选研究,E-mail:2443378879@qq.com
基金资助:
浙江省食品科学与工程重中之重一级学科开放项目（2017SIAR219）

Virtual Screening and Activity Evaluation of Multi-target Antibacterial Lead Compounds

CAI Jun-jun, YUAN Tian-qing, YANG Yin-ping, GAO Shuang, GONG Xing-wen*

School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China

Received:2017-09-29 Online:2018-07-23 Published:2018-07-23

摘要/Abstract

摘要：

铜绿假单胞菌和大肠杆菌是医院和兽医临床上常见的病原菌，容易造成人类和动物感染，给疾病治疗和经济发展带来极大的挑战。为了开发出靶向铜绿假单胞菌和大肠杆菌黏肽合成酶（PBPs）的新型先导化合物，笔者以铜绿假单胞菌PBP3和大肠杆菌PBP1b、PBP4、PBP5作为靶点，针对ZINC数据库，使用分子对接软件DOCK6.5进行了虚拟筛选。之后，根据得分情况和结构分析，找出了具有全新结构的先导化合物，进行了有机合成，并检验了抑菌效果。经过以Grid score为评价标准的初次筛选后，所有得分数值低于-125.6 kJ·mol^-1的化合物进入二次筛选，并进行Amber score打分，最终获得约200个得分数值低于-83.7 kJ·mol^-1的化合物。对这些化合物的结构进行分析后，以ZINC00053282为先导化合物进行了合成和结构验证。抑菌试验结果表明，筛选出的先导化合物对革兰阳性和阴性菌均具备抑菌活性，且抑菌效果优于对照组的磺胺嘧啶。筛选出的先导化合物具有全新的化学结构，可以作为候选抗菌药物，经进一步结构改造，有望用于解决日益严重的细菌耐药性问题。

Abstract:

Pseudomonas aeruginosa and Escherichia coli are two kinds of common pathogenic bacteria existed extensively in hospitals and veterinary clinics. They can infect both human and animals and brought great challenges to disease treatment and economic development. In order to obtain novel lead compounds targeting to penicillin-binding proteins(PBPs) of P. aerμginosa and E. coli, molecular docking was performed using UCSF DOCK 6.5 against ZINC database. PBP3 of Pseudomonas aeruginosa and PBP1b, PBP4, and PBP5 of Escherichia coli were chosen as the docking targets. Lead compounds with high scores and novel structures were selected for organic synthesis. Their antibacterial activities were evaluated according to their minimum inhibitory concentrations(MIC). Grid score was used for the first round of virtual screening, while lead compounds with grid scores lower than -125.6 kJ·mol^-1 were subjected to second round of screening. Amber score was used for the second round of virtual screening. Finally, approximately 200 compounds with amber score lower than -83.7 kJ·mol^-1 were screened out. In view of the structural novelty, lead compound ZINC00053282 was selected for synthesis. The result of antibacterial assay indicated that it could inhibit both Gram-positive and Gram-negative bacteria, with an activity better than sulfadiazine. These results mean that this lead compound is an potential antibacterial drug and might be used to solve the drug resistance problem.

中图分类号:

R965.1

蔡珺珺, 袁田青, 杨银萍, 高双, 宫兴文. 多靶点的抗菌先导化合物的虚拟筛选及活性研究[J]. 畜牧兽医学报, 2018, 49(7): 1500-1510.

CAI Jun-jun, YUAN Tian-qing, YANG Yin-ping, GAO Shuang, GONG Xing-wen. Virtual Screening and Activity Evaluation of Multi-target Antibacterial Lead Compounds[J]. ACTA VETERINARIA ET ZOOTECHNICA SINICA, 2018, 49(7): 1500-1510.

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参考文献

[1] LIVERMORE D M. Has the era of untreatable infections arrived?[J].J Antimicrob Chemother, 2009, 64(S1):i29-i36.
[2] SUÁREZ C, PEÑA C, TUBAU F, et al. Clinical impact of imipenem-resistant Pseudomonas aeruginosa bloodstream infections[J].J Infect, 2009, 58(4):285-290.
[3] 韩伟, 张铁, 王春光, 等.大肠埃希菌耐药机制研究进展[J].动物医学进展, 2006, 27(1):51-53.
HAN W, ZHANG T, WANG C G, et al. Progress on the drug resistance of Escherichia coli[J].Progress in Veterinary Medicine, 2006, 27(1):51-53. (in Chinese)
[4] VAN DEN BOGAARD A E, WILLEMS R, LONDON N, et al. Antibiotic resistance of faecal enterococci in poultry,poultry farmers and poultry slaughterers[J].J Antimicrob Chemother, 2002, 49(3):497-505.
[5] VANTARAKIS A, VENIERI D, KOMNINOU G, et al.Differentiation of faecal Escherichia coli from humans and animals by multiple antibiotic resistance analysis[J]. Lett Appl Microbiol, 2006, 42(1):71-77.
[6] ZAPUN A, CONTRERAS-MARTEL C, VERNET T. Penicillin-binding proteins and β-lactam resistance[J].FEMS Microbiol Rev, 2008, 32(2):361-385.
[7] 熊亚莉, 范昕建.青霉素结合蛋白研究进展[J].国外医药(抗生素分册), 2004, 25(5):193-197.
XIONG Y L, FAN X J. Research progress of penicillin binding protein[J].Foreign Medicine (Antibiotic Partition), 2004, 25(5):193-197. (in Chinese)
[8] CHEN W, ZHANG Y M, DAVIES C. Penicillin-binding protein 3 is essential for growth of Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother, 2017, 61(1):1616-1651.
[9] PEPPER E D, FARRELL M J, FINKEL S E. Role of penicillin-binding protein 1b in competitive stationary-phase survival of Escherichia coli[J].FEMS Microbiol Lett, 2006, 263(1):61-67.
[10] MEBERG B M, PAULSON A L, PRIYADARSHINI R, et al. Endopeptidase penicillin-binding proteins 4 and 7 play auxiliary roles in determining uniform morphology of Escherichia coli[J]. J Bacteriol, 2004, 186(24):8326-8336.
[11] NELSON D E, YOUNG K D. Penicillin binding protein 5 affects cell diameter, contour, and morphology of Escherichia coli[J]. J Bacteriol, 2000, 182(6):1714-1721.
[12] GHOSH A S, YOUNG K D. Sequences near the active site in chimeric penicillin binding proteins 5 and 6 affect uniform morphology of Escherichia coli[J].J Bacteriol, 2003, 185(7):2178-2186.
[13] ZERVOSEN A, SAUVAGE E, FRōRE J M, et al. Development of new drugs for an old target-the penicillin binding proteins[J]. Molecules (Basel, Switzerland), 2012, 17(12):12478-12505.
[14] JUAN C, MACIÁ M D, GUTIÉRREZ O, et al. Molecular mechanisms of β-lactam resistance mediated by AmpC hyperproduction in Pseudomonas aeruginosa clinical strains[J]. Antimicrob Agents Chemother, 2005, 49(11):4733-4738.
[15] YORDANOV D, STRATEVA T. Pseudomonas aeruginosa-a phenomenon of bacterial resistance[J].J Med Microbiol, 2009, 58(9):1133-1148.
[16] SÁENZ Y, ZARAZAGA M, BRIÑAS L, et al. Antibiotic resistance in Escherichia coli isolates obtained from animals,foods and humans in Spain[J]. Int J Antimicrob Agents, 2001, 18(4):353-358.
[17] KONG K F, SCHNEPER L, MATHEE K. Beta-lactam antibiotics:From antibiosis to resistance and bacteriology[J]. APMIS, 2010, 118(1):1-36.
[18] 张珍珍,吴俊伟,魏述永,等.动物源大肠杆菌超广谱β-内酰胺酶与头孢菌素酶基因型分析[J].畜牧兽医学报,2009,40(6):898-903.
ZHANG Z Z, WU J W, WEI S Y,et al. Analysis of genotype of Escherichina coli-produacing ESBLs and Apmc β-lactamases isolated from farm animals[J].Acta Veterinaria et Zootechnica Sinica, 2009,40(6):898-903. (in Chinese)
[19] 叶德举, 罗小民, 沈建华, 等.先导化合物的发现——整合计算机虚拟筛选、化学合成和生物测试方法[J].化学进展, 2007, 19(12):1939-1946.
YE D J, LUO X M, SHEN J H, et al. Discovering potential drug leads via docking, synthesis and bioassay[J]. Progress in Chemistry, 2007, 19(12):1939-1946. (in Chinese)
[20] SHOICHET B K.Virtual screening of chemical libraries[J].Nature,2004,432(7019):862-865.
[21] 侯廷军.计算机辅助药物分子设计方法研究[D].北京:北京大学, 2002.
HOU T J. Study on computer-aided drug molecular design[D]. Beijing:Peking University, 2002. (in Chinese)
[22] SPYRAKIS F, COZZINI P, KELLOGG G E, et al. Docking and scoring in drug discovery[M]//ABRAHAM D J, ROTELLA D P. Burger's medicinal chemistry and drug discovery. Canada:John Wiley & Sons, Inc., 2003:601-684.
[23] WASZKOWYCZ B, CLARK D E, GANCIA E. Outstanding challenges in protein-ligand docking and structure-based virtual screening[J]. Wiley Interdiscip Rev Comput Mol Sci, 2011, 1(2):229-259.
[24] IMPERIO D, GIOVENZANA G B, LAW G I, et al. Synthesis and comparative anion binding profiles of two di-aqua Eu(iii) complexes[J]. Dalton Trans, 2010, 39(41):9897-9903.
[25] FUNFUENHA W, PHAKHODEE W, PATTARAWARAPAN M. Facile and efficient synthesis of C₂-symmetrical 1,3,5-triazine polycarboxylate ligands under microwave irradiation[J]. Tetrahedron, 2014, 70(35):5415-5419.
[26] 喻召武. 靶向铜绿假单胞菌粘肽合成酶PBP3的抗菌先导化合物的虚拟筛选与活性研究[D]. 杭州:浙江工商大学, 2016.
YU Z W. Virtual screening and activity studies of antimicrobial lead compounds targeting to penicillin-binding protein 3 of Pseudomonas aeruginosa[D].Hangzhou:Zhejiang Gongshang University, 2016. (in Chinese)
[27] 安艳冬.大肠杆菌PBP1b和铜绿假单胞菌PBP3的表达纯化[D].杭州:浙江工商大学, 2015.
AN Y D. Expression and purification of PBP1B from Escherichia coli and PPBP3 from Pseudomonas aeruginosa[D]. Hangzhou:Zhejiang Gongshang University, 2015. (in Chinese)
[28] 吴可柱,李昆,李爱秀.虚拟筛选技术与新药开发[J].武警医学院学报, 2011, 20(5):415-419.
WU K Z, LI K, LI A X. Virtual screening and new drug discovery[J]. Journal of Armed Police Medical College, 2011, 20(5):415-419. (in Chinese)
[29] RECACHA R, COSTANZO M J,MARYANOFF B E, et al. Crystal structure of human carbonic anhydrase Ⅱ complexed with an anti-convulsant sugar sulphamate[J].Biochem J, 2002, 361(3):437-441.
[30] GUIDO R V, OLIVA G, ANDRICOPULO A D. Virtual screening and its integration with modern drug design technologies[J]. Curr Med Chem, 2008, 15(1):37-46.
[31] LIU A L, CAO H P, DU G H. Drug screening for influenza neuraminidase inhibitors[J].Science in China Ser. C Life Sciences, 2005, 48(1):1-5.

多靶点的抗菌先导化合物的虚拟筛选及活性研究

Virtual Screening and Activity Evaluation of Multi-target Antibacterial Lead Compounds

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