Advances in the computational development of hepatitis B virus capsid assembly modulators

The capsid protein (Cp) of hepatitis B virus (HBV) is crucial for the nucleocapsid formation, viral DNA replication, and virus–host cell interactions necessary for HBV persistence. Capsid assembly modulators (CAMs) target Cp dimer–dimer interactions, thereby inhibiting the reverse transcription of pregenomic RNA and the synthesis of relaxed circular DNA, leading to a reduction in covalently closed circular DNA amplification. This review highlights the use of molecular docking, quantitative structure–activity relationship (QSAR), and machine learning-based QSAR models, and molecular dynamics simulations, in CAM discovery and optimization. We aim to provide strategies for CAM discovery, optimization, and clinical translation from a computer-aided drug design perspective, thereby contributing to efforts toward a functional cure for HBV.