高等学校化学学报 ›› 2018, Vol. 39 ›› Issue (4): 701.doi: 10.7503/cjcu20170392

• 有机化学 • 上一篇    下一篇

ApIV 3C蛋白酶抑制剂的虚拟筛选及活性测定

史艳丽1, 刘宇博1, 吴思晋2, 刘亚军1, 张嘉宁1, 李文利1()   

  1. 1. 大连理工大学生命与医药学院, 盘锦 124221
    2. 大连理工大学生命科学与技术学院, 分子药物中心, 大连 116023
  • 收稿日期:2017-06-20 出版日期:2018-04-10 发布日期:2018-03-16
  • 作者简介:联系人简介: 李文利, 男, 博士, 副教授, 博士生导师, 主要从事分子生物学方面的研究. E-mail:biolwl@dlut.edu.cn
  • 基金资助:
    国家自然科学基金(批准号: 31570802, 21502015)资助

Virtual Screening and Activity Verification of Novel Inhibitors of ApIV 3C Protease

SHI Yanli1, LIU Yubo1, WU Sijin2, LIU Yajun1, ZHANG Jianing1, LI Wenli1,*()   

  1. 1. School of Life Science and Medicine, Dalian University of Technology, Panjin 124221, China
    2. Center for Molecular Medicine, School of Life Science and Biotechnology,Dalian University of Technology, Dalian 116023, China
  • Received:2017-06-20 Online:2018-04-10 Published:2018-03-16
  • Contact: LI Wenli E-mail:biolwl@dlut.edu.cn
  • Supported by:
    † Supported by the National Natural Science Foundation of China(Nos.31570802, 21502015)

摘要:

运用Discovery Studio 4.5软件, 通过同源建模及分子动力学优化获得柞蚕小吐白水软化病毒(ApIV)3C蛋白酶的3D结构; 通过分子对接对天然产物库进行虚拟筛选, 得到1个ApIV 3C蛋白酶的有效抑制剂3',4',5,7-四羟基异黄酮(Orobol). 分子对接和分子动力学(MD)模拟结果进一步证明Orobol能稳定结合于ApIV 3C蛋白酶的结合口袋处. 体内外的ApIV病毒抑制实验结果表明, Orobol具有良好的抗病毒活性.

关键词: 柞蚕, 柞蚕吐白水软化病毒, 3C蛋白酶, 抑制剂, 虚拟筛选

Abstract:

Antheraea pernyi iflavirus(ApIV) is an important cause of antheraea pernyi vomiting disease(AVD) which is seriously harming the production of Antheraea pernyi(A. pernyi) industry in China. ApIV is a single-stranded, positive-sense RNA virus, belong to the picornavirida family. Due to the significant role of 3C protease in virus replication, it is considered to be an attractive drug target for developing antiviral therapeutic agents. Although great efforts have been made to develop 3C protease inhibitors, no effective anti-viral therapy for the prevention or treatment of diseases caused by ApIV infection is available. In this study, an effective inhibitor of ApIV 3C protease, 3',4',5,7-tetrahydroxyisoflavone(Orobol), was identified through virtual screening using molecular docking against natural product library. And the binding mode of Orobol with ApIV 3C protease was stable through molecular docking and molecular dynamics simulation(MD). The biological data displayed that the inhibition ratio of virus replication was stronger with the increase of the concentration of Orobol. And when the concentration of Orobol was 10 μg/mL, the inhibition ratio reached 80.5%. In vivo assay also demonstrated that Orobol could inhibit viral replication in spodoptera frugiperda cell(Sf9) cells. Those results proved that Orobol was a novel inhibitor for the disease of antheraea pernyi caused by ApIV infections.

Key words: Antheraea pernyi, Antheraea pernyi iflavirus, 3C Protease, Inhibitor, Virtual screening

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