The World Health Organization has designated Zika virus (ZIKV) as a dangerous, mosquito-borne pathogen that can cause severe developmental defects. The primary goal of this work was identification of small molecules as potential ZIKV inhibitors that target the viral envelope glycoprotein (ZIKV E) involved in membrane fusion and viral entry. A homology model of ZIKV E containing the small molecule β-octyl glucoside (BOG) was constructed, on the basis of an analogous X-ray structure from dengue virus, and >4 million commercially available compounds were computationally screened using the program DOCK6. A key feature of the screen involved the use of similarity-based scoring to identify inhibitor candidates that make similar interaction energy patterns (molecular footprints) as the BOG reference. Fifty-three prioritized compounds underwent experimental testing using cytotoxicity, cell viability, and tissue culture infectious dose 50% (TCID50) assays. Encouragingly, relative to a known control (NITD008), six compounds were active in both the cell viability assay and the TCID50 infectivity assay, and they showed activity in a third caspase activity assay. In particular, compounds 8 and 15 (tested at 25 μM) and compound 43 (tested at 10 μM) appeared to provide significant protection to infected cells, indicative of anti-ZIKV activity. Overall, the study highlights how similarity-based scoring can be leveraged to computationally identify potential ZIKV E inhibitors that mimic a known reference (in this case BOG), and the experimentally verified hits provide a strong starting point for further refinement and optimization efforts.

中文翻译：

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使用同源性建模和基于相似性的靶向糖蛋白E筛选筛选Zika病毒抑制剂。

世界卫生组织已将寨卡病毒（ZIKV）指定为危险的蚊媒病原体，可导致严重的发育缺陷。这项工作的主要目的是鉴定小分子作为潜在的ZIKV抑制剂，它们靶向与膜融合和病毒进入有关的病毒包膜糖蛋白（ZIKV E）。基于登革热病毒的类似X射线结构，构建了包含小分子β-辛基葡糖苷（BOG）的ZIKV E的同源性模型，并使用DOCK6程序计算筛选了超过400万种可商购的化合物。该屏幕的关键特征在于使用基于相似性的评分来识别候选候选物，这些候选物具有相似的相互作用能模式（分子足迹）作为BOG参考。对53种优先化合物进行了细胞毒性，细胞生存力和组织培养物感染剂量50％（TCID50）分析的实验测试。令人鼓舞的是，相对于已知的对照（NITD008），六种化合物在细胞活力测定和TCID50传染性测定中均具有活性，并且在第三种caspase活性测定中均具有活性。特别是化合物8和15（在25μM下测试）和化合物43（在10μM下测试）似乎对感染的细胞提供了显着的保护，表明其抗ZIKV活性。总的来说，这项研究强调了如何利用基于相似性的评分来计算识别潜在的模仿已知参考的ZIKV E抑制剂（在这种情况下为BOG），并且经过实验验证的命中为进一步的精炼和优化工作提供了强大的起点。