Computational Docking Study of p7 Ion Channel from HCV Genotype 3 and Genotype 4 and Its Interaction with Natural Compounds

Abstract

BackgroundThe current standard care therapy for hepatitis C virus (HCV) infection consists of two regimes, namely interferon-based and interferon-free treatments. The treatment through the combination of ribavirin and pegylated interferon is expensive, only mildly effective, and is associated with severe side effects. In 2011, two direct-acting antiviral (DAA) drugs, boceprevir and telaprevir, were licensed that have shown enhanced sustained virologic response (SVR) in phase III clinical trial, however, these interferon-free treatments are more sensitive to HCV genotype 1 infection. The variable nature of HCV, and the limited number of inhibitors developed thus aim in expanding the repertoire of available drug targets, resulting in targeting the virus assembly therapeutically.AimWe conducted this study to predict the 3D structure of the p7 protein from the HCV genotypes 3 and 4. Approximately 63 amino acid residues encoded in HCV render this channel sensitive to inhibitors, making p7 a promising target for novel therapies. HCV p7 protein forms a small membrane known as viroporin, and is essential for effective self-assembly of large channels that conduct cation assembly and discharge infectious virion particles.MethodIn this study, we screened drugs and flavonoids known to disrupt translation and production of HCV proteins, targeted against the active site of p7 residues of HCV genotype 3 (GT3) (isolatek3a) and HCV genotype 4a (GT4) (isolateED43). Furthermore, we conducted a quantitative structure–activity relationship and docking interaction study.ResultsThe drug NB-DNJ formed the highest number of hydrogen bond interactions with both modeled p7 proteins with high interaction energy, followed by BIT225. A flavonoid screen demonstrated that Epigallocatechin gallate (EGCG), nobiletin, and quercetin, have more binding modes in GT3 than in GT4. Thus, the predicted p7 protein molecule of HCV from GT3 and GT4 provides a general avenue to target structure-based antiviral compounds.ConclusionsWe hypothesize that the inhibitors of viral p7 identified in this screen may be a new class of potent agents, but further confirmation in vitro and in vivo is essential. This structure-guided drug design for both GT3 and GT4 can lead to the identification of drug-like natural compounds, confirming p7 as a new target in the rapidly increasing era of HCV.

Quercetin: Antiviral Significance and Possible COVID-19 Integrative Considerations

“…61,62 Molecular docking analysis also found that Que may interact with HCV NS3 helicase, NS5B polymerase, and p7 proteins. 63,64 These results correlate with experimental studies showing the anti-HCV activity of Que through inhibition of NS3 helicase and heat-shock proteins. [65][66][67] A phase I trial investigated the potential antiviral effect of Que among patients with hepatitis C virus (HCV).…”

Flavonoids: promising natural compounds against viral infections

“…In addition, in silico analysis revealed that quercetin may be a potential inhibitor of the neuraminidase of influenza A H1N1 and H7N9 viruses [79,80]. Molecular docking analysis also found that quercetin may interact with HCV NS3 helicase, NS5B polymerase and p7 proteins [34,86]. These results correlate with experimental studies showing the anti-HCV activity of quercetin through inhibition of NS3 helicase and heat shock proteins [4,81].…”

Inhibition of SARS CoV Envelope Protein by Flavonoids and Classical Viroporin Inhibitors

“…Some 3a-inhibitory kaempferol derivatives were identified, the glycoside juglanin being the most efficient ( Schwarz et al, 2014 ). A computational docking study of p7 ion channel from HCV Genotype 3 and Genotype 4 tested different flavonoids including Epigallocatechin-3-gallate, apigenin, naringenin, luteolin, quercetin, ladanein, silymarin, honokiol, and nobiletin, showing the existence of flavonoid binding pockets in different viroporins ( Mathew et al, 2015 ). Our results identify quercetin and EGCG as potential ligands and inhibitors of the SARS-CoV E protein.…”