Evaluation of Potential Anti-Hepatitis A Virus 3C Protease Inhibitors Using Molecular Docking

Abstract

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis worldwide and occasionally causes acute liver failure and can lead to death in the absence of liver transplantation. Although HAV vaccination is available, the prevalence of HAV vaccination is not adequate in some countries. Additionally, the improvements in public health reduced our immunity to HAV infection. These situations motivated us to develop potentially new anti-HAV therapeutic options. We carried out the in silico screening of anti-HAV compounds targeting the 3C protease enzyme using the Schrodinger Modeling software from the antiviral library of 25,000 compounds to evaluate anti-HAV 3C protease inhibitors. Additionally, in vitro studies were introduced to examine the inhibitory effects of HAV subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in hepatoma cell lines using luciferase assays and real-time RT-PCR. In silico studies enabled us to identify five lead candidates with optimal binding interactions in the active site of the target HAV 3C protease using the Schrodinger Glide program. In vitro studies substantiated our hypothesis from in silico findings. One of our lead compounds, Z10325150, showed 47% inhibitory effects on HAV genotype IB subgenomic replicon replication and 36% inhibitory effects on HAV genotype IIIA HA11-1299 replication in human hepatoma cell lines, with no cytotoxic effects at concentrations of 100 μg/mL. The effects of the combination therapy of Z10325150 and RNA-dependent RNA polymerase inhibitor, favipiravir on HAV genotype IB HM175 subgenomic replicon replication and HAV genotype IIIA HA11-1299 replication showed 64% and 48% inhibitory effects of HAV subgenomic replicon and HAV replication, respectively. We identified the HAV 3C protease inhibitor Z10325150 through in silico screening and confirmed the HAV replication inhibitory activity in human hepatocytes. Z10325150 may offer the potential for a useful HAV inhibitor in severe hepatitis A.

Computer-Aided Design and Synthesis of (Functionalized quinazoline)–(α-substituted coumarin)–arylsulfonate Conjugates against Chikungunya Virus

“…Therefore, the free energy of the overall system had to be minimized by computations to find the optimized conformation of the conjugated compounds and nsP3. Understanding of the binding behavior and characters would assist us in designing an effective agent against CHIKV [ 42 , 43 ].…”

Recent advances in hepatitis A virus research and clinical practice guidelines for hepatitis A virus infection in Japan

“…[215][216][217][218] Effects of other anti-HAV drugs, including HAV 3C protease inhibitors, have been reported in vitro. [219][220][221][222][223] These antiviral candidates, and their efficacy and roles as PEP, should be examined in vivo.…”

“…Amantadine also inhibits HAV internal ribosome entry site activity and induces autophagy of hepatocytes, resulting in inhibition of HAV replication 215–218 . Effects of other anti‐HAV drugs, including HAV 3C protease inhibitors, have been reported in vitro 219–223 . These antiviral candidates, and their efficacy and roles as PEP, should be examined in vivo .…”

Molecular Mechanism of Chronic Viral and Non-Viral Liver Diseases

“…Local catabolism of the amino acid tryptophan by indoleamine 2,3-dioxygenase (IDO) also seems an important mechanism of regulating T cell immunity [ 8 ]. SPRi screening assay may also be useful for investigating the molecular mechanism of drug development, as well as other modalities, such as in silico molecular docking or reverse LIGHTHOUSE analysis [ 9 , 10 , 11 ].…”