Development of novel HBV capsid assembly modifiers through molecular dynamics, docking, and experiments

Hepatitis B Virus (HBV) is the leading cause of liver complications, including cirrhosis, hepatocellular carcinoma, and liver failure. Interfering with the self-assembly process of virus nucleocapsid is a promising approach for the development of the novel antiviral agents. Starting from microsecond-scale molecular dynamic simulations of a tetramer of the HBV capsid protein Cp149, we identified three novel conformations for docking based on their pocket volume and principal component analysis of inter-dimer motions. Compounds were selected from the DivV set of NCI and ZINC0.9 databases for experimental testing according to their docking scores for the selected pocket. Combining molecular dynamics simulations and in vitro testing, we discovered several novel compounds with moderate activity. Additionally, transmission electron microscopy and capsid assembly experiments suggest that our compounds possess a novel mechanism for assembly modulation, potentially opening new avenues for HBV inhibition.