Discovery of novel HBV capsid assembly modulators by structure-based virtual screening and bioassays
Discovery of novel HBV capsid assembly modulators by structure-based virtual screening and bioassays
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通过基于结构的虚拟筛选和生物测定发现新型 HBV 衣壳组装调节剂
DOI：
10.1016/j.bmc.2021.116096
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Tingjun Hou
中科院分区：
文献类型：
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作者：
Yuan Wang;Zhe Wang;Jiacheng Liu;Yunwen Wang;Rui Wu;Rong Sheng;Tingjun Hou
HBV衣壳组装被认为是抗HBV治疗的一个有吸引力的潜在靶点。在这项研究中，我们通过基于结构的虚拟筛选和生物测定发现了新型HBV衣壳组装调节剂（CAMs）。共获得16个结构各异的化合物，其中3个化合物在20 μM下抑制率为bb50 %。以最有效的化合物di -1 - 7（EC50= 5.6±0.1µM）为基础，通过子结构搜索策略进行进一步的先导物优化，得到化合物di -2 - 9的EC50值为1.8±0.6 μM。在双分子荧光互补（BiFC）实验中，化合物ii -2 - 9通过破坏HBV衣壳相互作用来抑制HBV。综上所述，本研究为发现新型CAMs提供了一种高效的途径，2-芳基-4-喹啉酰胺衍生物可作为开发新型抗hbv药物的起点。
HBV capsid assembly has been regarded as an attractive potential target for anti-HBV therapy. In this study, we discovery the Novel HBV capsid assembly modulators (CAMs) through structure-based virtual screening and bioassays. A total of 16 structurally diverse compounds were purchased and assayed, including three compounds with inhibition rate > 50% at 20 μM. Further lead optimization based on the most potent compoundII-1–7(EC50= 5.6 ± 0.1 µM) were performed by using substructure searching strategy, resulting in compoundII-2–9with an EC50value of 1.8 ± 0.6 μM. In bimolecular fluorescence complementation (BiFC) assay, compoundII-2–9inhibited the HBV by disrupting the HBV capsid interactions. In summary, this study provides a highly efficient way to discover novel CAMs, and 2-aryl-4-quinolyl amide derivatives could serve as the starting point for development of novel anti-HBV drugs.