Chronic Hepatitis Beta virus (HBV) infection is a major cause of liver damage and liver cancer. Recently HBV capsid assembly has become an attractive target for new antiviral drugs. Two major classes of compounds: phenylpropenamides and heteroaryldihydropyrimidines (HAP) have been shown to prevent the formation of normal capsids by binding to the intermediates of the capsid assembly. While phenylpropenamides accelerate assembly of normal capsids, HAP compounds misdirect the assembly into non-capsid structures. The reason for the different assembly effects is presently not well understood. Here we have used MD simulations to study important early assembly intermediates of the capsid assembly, i.e., tetramers and hexamers of the capsid protein, with and without different assembly modifiers. It was discovered that assembly modifiers significantly alter the structure of the early intermediates. Distinct structural changes were observed for accelerating and for misdirecting modifiers. It was also found that apo tetramers and hexamers are very flexible, adopting conformations distinct from crystal structures. Therefore, we used principal component analysis to select tetramer conformations from our simulations for docking. Experimental testing of our top candidates confirmed the discovery of several novel compounds with moderate activity against HBV.

Rational development of HBV capsid assembly modifiers aided by molecular dynamics

256th National Meeting (2018)

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