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

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.