Discovery of novel HBV capsid assembly modulators by structure-based virtual screening and bioassays

Yuan Wang; Zhe Wang; Jiacheng Liu; Yunwen Wang; Rui Wu; Rong Sheng; Tingjun Hou

doi:10.1016/j.bmc.2021.116096

Discovery of novel HBV capsid assembly modulators by structure-based virtual screening and bioassays

Bioorg Med Chem. 2021 Apr 15:36:116096. doi: 10.1016/j.bmc.2021.116096. Epub 2021 Mar 4.

Authors

Yuan Wang¹, Zhe Wang¹, Jiacheng Liu¹, Yunwen Wang², Rui Wu³, Rong Sheng⁴, Tingjun Hou⁵

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: shengr@zju.edu.cn.
⁵ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China. Electronic address: tingjunhou@zju.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Capsid Proteins / antagonists & inhibitors*
Capsid Proteins / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Hep G2 Cells
Hepatitis B virus / drug effects*
Hepatitis B virus / metabolism
Humans
Microscopy, Fluorescence
Molecular Structure
Structure-Activity Relationship

Substances

Antiviral Agents
Capsid Proteins