Structure-based Design of Novel Hepatitis B Virus Capsid Assembly Modulators

[Display omitted] •Capsid Assembly Modulators are promising agents for curing chronic HBV infection.•Target-based in silico screening study leads to the discovery of novel HBV CAMs.•Lead compounds show in vitro potency in the sub-micromolar range.•A novel series of pyrazines is classified as non-HAP like HBV CAMs. Small-molecule capsid assembly modulators (CAMs) have been recently recognized as promising antiviral agents for curing chronic hepatitis B virus (HBV) infection. A target-based in silico screening study is described, aimed towards the discovery of novel HBV CAMs. Initial optimization of four weakly active screening hits was performed via focused library synthesis. Lead compound 42 and close analogues 56 and 57 exhibited in vitro potency in the sub- and micromolar range along with good physico-chemical properties and were further evaluated in molecular docking and mechanism of action studies.