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Discovery and Computational Analyses of Novel Small Molecule Zika Virus Inhibitors.

  • Author(s): Zhu, Siyu
  • Zhang, Chaozai
  • Huang, Lina S
  • Zhang, Xing-Quan
  • Xu, Yan
  • Fang, Xiong
  • Zhou, Jiao
  • Wu, Meixian
  • Schooley, Robert T
  • Huang, Ziwei
  • An, Jing
  • et al.
Abstract

Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain-Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC50 values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure-activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.

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