Rational Development of a New Type of HBV Capsid Inhibitors by a Combination of Microsecond-Scale Molecular Dynamics and Docking

Abstract

Chronic infection by the Hepatitis B virus (HBV) has no cure and is a major cause of liver damage and liver cancer. According to recent studies, targeting HBV capsid assembly can inhibit the virus growth. The HBV capsid proteins assemble via tetramer intermediates, with two dimer subunits and a pocket between them. Several compounds can bind to this pocket and alter orientation of the two subunits, which in turn inhibits virus growth by either accelerating the capsid assembly, or causing the proteins to assemble into non-capsid linear polymers. However, a greater therapeutic potential could be achieved by rationally designing such compounds.Here, we propose HBV capsid inhibitors from combined molecular dynamics and docking methodologies. We targeted the limiting step in the capsid formation of HBV, which is formation of a hexamer from a tetramer. Microsecond-long tetramer simulations showed slow motions of the two dimer subunits and large fluctuations in the size of the pocket between them. Based on principal component analysis of the tetramer motion, we selected a structure that was unfavorable for trimer formation and had a larger pocket volume compared to the assembled structure. In order to find potential inhibitors we docked over 100,000 compounds to the pocket in the selected structure. The top candidate compounds were selected based on docking score and surface area. The drug-protein complexes were further evaluated with molecular dynamics simulations.