Abstract
Chronic hepatitis B virus (HBV) infection is a global problem. The loss of hepatitis B surface antigen (HBsAg) in serum is a therapeutic end point. Prolonged therapy with nucleoside/nucleotide analogues targeting the HBV-polymerase may lead to resistance and rarely results in the loss of HBsAg. Therefore, inhibitors targeting HBsAg may have potential therapeutic applications. Here, we used computational virtual screening, docking, and molecular dynamics simulations to identify potential small molecule inhibitors against HBsAg. After screening a million molecules from ZINC database, we identified small molecules with potential anti-HBV activity. Subsequently, cytotoxicity profiles and anti-HBV activities of these small molecules were tested using a widely used cell culture model for HBV. We identified a small molecule (ZINC20451377) which binds to HBsAg with high affinity, with a KD of 65.3 nM, as determined by Surface Plasmon Resonance spectroscopy. Notably, the small molecule inhibited HBsAg production and hepatitis B virion secretion (10 μM) at low micromolar concentrations and was also efficacious against a HBV quadruple mutant (CYEI mutant) resistant to tenofovir. We conclude that this small molecule exhibits strong anti-HBV properties and merits further testing.
Highlights
Chronic hepatitis B virus (HBV) infection is a global problem
The refined structures were subjected to molecular dynamics simulations consisting of minimization heating followed by production of 20 ns
The structure which showed best ProTSAV score was further checked using R AMPAGE15 The Ramachandran plot for the final model was calculated which showed that only 2.8% of φ, ψ angles were in disallowed regions, 80.8% of the residues were in the most favoured region, and the remaining residues were in the allowed regions (Fig. 1C)
Summary
Chronic hepatitis B virus (HBV) infection is a global problem. The loss of hepatitis B surface antigen (HBsAg) in serum is a therapeutic end point. The small molecule inhibited HBsAg production and hepatitis B virion secretion (10 μM) at low micromolar concentrations and was efficacious against a HBV quadruple mutant (CYEI mutant) resistant to tenofovir. We conclude that this small molecule exhibits strong anti-HBV properties and merits further testing. We identified five potential small molecule inhibitors against HBsAg in the initial computational screening One of these small molecules (ZINC20451377) (Figure S1) binds HBsAg in vitro and reduced HBsAg levels and hepatitis B virion secretion in a widely used cell culture model for HBV. We have identified and validated a small molecule inhibitor that targets HBsAg resulting in the inhibition of hepatitis B virion secretion from wild-type and drug resistant HBV mutants
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