title: Discovering novel direct acting antiviral agents for HBV using in silico screening.
abstract: 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.
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan. Electronic address: m2079633@med.osaka-cu.ac.jp.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Hayakawa
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yano
authors.affiliation: Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 650-0017, Japan.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Tanahashi
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Enomoto
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tamori
authors.affiliation: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
authors.affiliation: Department of Biological Science, Chuo University, Tokyo 112-8551, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iwadate
authors.affiliation: Department of Biological Science, Chuo University, Tokyo 112-8551, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Umeyama
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000418:Albumins / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D002678:Chimera; D030562:Databases, Protein; D015195:Drug Design; D055808:Drug Discovery; D006515:Hepatitis B virus / Q000187:drug effects*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D062105:Molecular Docking Simulation; D063065:Organophosphonates / Q000494:pharmacology; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D000068698:Tenofovir
chemical_list: D000418:Albumins; D000998:Antiviral Agents; D008024:Ligands; D063065:Organophosphonates; D019259:Lamivudine; D000068698:Tenofovir; D000225:Adenine; C106812:adefovir dipivoxil
keywords: Hepatitis B virus; In silico screening; Reverse transcriptase