School of Life Sciences, Tsinghua University, Beijing 100084, China.
Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA.
Molecules. 2019 Apr 13;24(8):1465. doi: 10.3390/molecules24081465.
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 and ). They inhibited ZIKV infection with IC 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.
寨卡病毒（ZIKV）是黄病毒家族的一员，自巴西大规模流行以来引起了全球关注。寨卡病毒感染与小头症和吉兰-巴雷综合征等神经系统问题的关联促使人们进行了深入的病理学研究。然而，在发现有效的抗寨卡病毒治疗方法方面还有很长的路要走。在这项研究中，我们使用分子对接方法对基于寨卡病毒 NS3 解旋酶的国家癌症研究所（NCI）多样性集进行了计算机筛选。具有类药性的选定化合物进行了基于细胞的抗病毒测定，从而鉴定出两种新型先导化合物（分别命名为化合物 和 ）。它们以微摩尔级别的 IC 值抑制寨卡病毒感染（分别为 8.5 μM 和 15.2 μM）。这两种化合物的结合模式分析、绝对结合自由能计算和构效关系研究揭示了它们与寨卡病毒 NS3 解旋酶可能的相互作用，为进一步优化提供了机制基础。这两种新型小分子可能代表开发抗寨卡病毒抑制药物的新先导化合物。
