Discovering novel direct acting antiviral agents for HBV using in silico screening

• Published in: Biochemical and biophysical research communications 2015-01, Vol.456 (1), p.20-28
• Main Authors: Murakami, Yoshiki, Hayakawa, Michiyo, Yano, Yoshihiko, Tanahashi, Toshihito, Enomoto, Masaru, Tamori, Akihiro, Kawada, Norifumi, Iwadate, Mitsuo, Umeyama, Hideaki
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Albumins - chemistry; Animals; Antiviral Agents - pharmacology; Binding Sites; Cells, Cultured; Chimera; Databases, Protein; Drug Design; Drug Discovery; Hepatitis B virus; Hepatitis B virus - drug effects; Hepatitis B, Chronic - drug therapy; Humans; In silico screening; Lamivudine - pharmacology; Ligands; Liver - metabolism; Mice; Middle Aged; Molecular Docking Simulation; Organophosphonates - pharmacology; Protein Binding; Real-Time Polymerase Chain Reaction; Reverse transcriptase; Tenofovir
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.11.024

•We developed a novel drug candidate search system.•3D structure of target protein and drug database are required for this method.•This method can reduce time and expense to find drug candidates.•The anti-viral drug candidates were chosen efficiently by this method.•This method is applicable to screening of the drug candidates of other diseases. The treatments for chronic hepatitis B (CHB) are interferon and nucleoside analogues reverse transcriptase (RT) inhibitors. Because both treatments are less than ideal, we conducted to identify novel anti-viral agents for HBV-reverse transcriptase (HBV-RT). We determined the ligand-binding site of the HBV-RT by conducting a homological search of the amino acid sequence and then we also determined not only structural arrangement of the target protein but the target protein-binding site of the ligand using known protein–ligand complexes in registered in the protein data bank (PDB). Finally we simulated binding between the ligand candidates and the HBV-RT and evaluated the degree of binding (in silico screening). PXB cells derived from human-mouse chimeric mouse liver, infected with HBV were administrated with the candidates, and HBVDNA in the culture medium was monitored by realtime qPCR. Among compounds from the AKosSamples database, twelve candidates that can inhibit RT were also identified, two of which seem to have the potential to control HBV replication in vitro.