通过基于结构的虚拟筛选和生物测定发现新型HBV衣壳装配调

StephenW

Discovery of novel HBV capsid assembly modulators by structure-based virtual screening and bioassays
Yuan Wang  1 , Zhe Wang  1 , Jiacheng Liu  1 , Yunwen Wang  2 , Rui Wu  3 , Rong Sheng  4 , Tingjun Hou  5
Affiliations
Affiliations

    1
    College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
    2
    College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China.
    3
    Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China.
    4
    College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. Electronic address: [email protected].
    5
    College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. Electronic address: [email protected].

    PMID: 33721800 DOI: 10.1016/j.bmc.2021.116096

Abstract

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 compound II-1-7 (EC50 = 5.6 ± 0.1 µM) were performed by using substructure searching strategy, resulting in compound II-2-9 with an EC50 value of 1.8 ± 0.6 μM. In bimolecular fluorescence complementation (BiFC) assay, compound II-2-9 inhibited 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.

Keywords: 2-aryl-4-quinolyl amide; Capsid assembly modulators; Hepatitis B virus; Virtual screening.

Copyright © 2021 Elsevier Ltd. All rights reserved.

StephenW

通过基于结构的虚拟筛选和生物测定发现新型HBV衣壳装配调节剂
望网1，浙王1，刘家成1，王云文2，吴瑞3，荣盛4，侯廷军5
隶属关系
隶属关系

    1个
    浙江大学药学院，浙江杭州310058。
    2个
    浙江大学药学院，浙江杭州310058；浙江工业大学长三角地区绿色制药协同创新中心，杭州310014
    3
    浙江工业大学长三角地区绿色制药协同创新中心，杭州310014
    4
    浙江大学药学院，浙江杭州310058。电子地址：[email protected]。
    5
    浙江大学药学院，浙江杭州310058。电子地址：[email protected]。

    PMID：33721800 DOI：10.1016 / j.bmc.2021.116096

抽象的

HBV衣壳组装一直被认为是抗HBV治疗的诱人潜在靶标。在这项研究中，我们通过基于结构的虚拟筛选和生物测定法发现了新型HBV衣壳装配调节剂（CAM）。总共购买并分析了16种结构多样的化合物，包括3种在20μM时抑制率> 50％的化合物。通过使用子结构搜索策略，基于最有效的化合物II-1-7（EC50 = 5.6±0.1 µM）进一步进行铅优化，得到的化合物II-2-9的EC50值为1.8±0.6μM。在双分子荧光互补（BiFC）分析中，化合物II-2-9通过破坏HBV衣壳相互作用来抑制HBV。总而言之，这项研究提供了一种发现新型CAM的高效方法，并且2-芳基-4-喹啉基酰胺衍生物可以作为开发新型抗HBV药物的起点。

关键字：2-芳基-4-喹啉基酰胺;衣壳装配调节器；乙型肝炎病毒;虚拟筛选。

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