The NS2B-NS3 protease has been identified as an attractive target for drug development against Zika virus (ZIKV) and combined drug repurposing and structure-based virtual screening has improved the development of antiviral drugs. In this study, we performed a structure-based virtual screening of 1861 Food and Administration (FDA) approved drugs available in DrugBank by the selection and docking validation of crystal structure of ZIKV NS2B-NS3 protease (PDB ID 5H4I ) using Glide and DOCK 6 software. The antihistaminic chlorcyclizine (Grid score -24.8 kcal/mol) exhibited the most promising interaction with NS2B-NS3 protease in comparison to crystallography ligand (Grid score -15.6 kcal/mol) by interaction to Tyr161 by hydrophobic interactions in the binding site of NS2B-NS3 which is recognized as an important amino acid in substrate molecular recognition. Cytotoxicity and global antiviral activity assay in Vero cells by MTT method showed that chlorcyclizine reduced the ZIKV induced cytopathic effect (EC50 of 69.0 ± 7.3 μM and SI = 1.9), and explicit molecular dynamics simulations implemented on a NAMD program indicated great stability of chlorcyclizine in protease binding site, suggesting the repurposing of chlorcyclizine as a promising finding in anti-ZIKV drug development.

中文翻译：

---

通过基于结构的虚拟筛选和药物再利用方法鉴定寨卡病毒NS2B-NS3蛋白酶抑制剂。

NS2B-NS3蛋白酶已被确定为对抗Zika病毒（ZIKV）的药物开发的有吸引力的目标，结合药物重用和基于结构的虚拟筛选已改善了抗病毒药物的开发。在这项研究中，我们使用Glide和DOCK 6对ZIKV NS2B-NS3蛋白酶（PDB ID 5H4I）的晶体结构进行选择和对接验证，从而对1861年获得美国食品与药物管理局（FDA）批准的药物进行了基于结构的虚拟筛选。软件。与晶体学配体相比，抗组胺氯环嗪（格氏评分-24.8 kcal / mol）与NS2B-NS3蛋白酶表现出最有希望的相互作用（格氏评分-15）。通过在NS2B-NS3的结合位点通过疏水相互作用与Tyr161相互作用来实现6 kcal / mol）（这被认为是底物分子识别中的重要氨基酸）。MTT法检测Vero细胞的细胞毒性和整体抗病毒活性表明，氯环嗪可降低ZIKV诱导的细胞病变效应（EC50为69.0±7.3μM，SI = 1.9），在NAMD程序上进行的明确分子动力学模拟表明，氯环嗪具有很好的稳定性。蛋白酶结合位点，表明氯霉素的重新用途是抗ZIKV药物开发中的一个有前途的发现。