In Silico Studies of the Hepatitis B Virus Polymerase: Efforts to Identify Novel Drug Binding Sites to Inhibit HBV Replication.

Hepatitis B virus (HBV) replicates via reverse transcription, a reaction catalyzed by the HBV polymerase (P) protein. P is a multidomain protein consists of terminal protein, spacer, reverse transcriptase, and ribonuclease H domains. We used a predicted structural model of HBV P and computationally identified potential non-nucleos(t)ide reverse transcriptase inhibitor (NNRTI) sites. Out of the three potential NNRTI sites, we selected Site 3 for virtual high throughput screening of 837,000 virtual compounds. We selected 53 compounds considering their docking scores, ligand uniqueness, stability and rigidity for screening in HBV replication inhibition assay, but all of them failed to suppress the HBV reverse transcription. Molecular dynamic simulations showed that Site 3 binding pocket is not conformationally stable even after binding of the ligand. This study indicates that additional potential NNRTI sites should be explored, and that rigorous molecular dynamic simulations studies should be performed before virtual compound screening.