Molecular docking, ADMET analysis, and bioactivity studies of phytochemicals from Phyllanthus niruri as potential inhibitors of hepatitis C virus NSB5 polymerase

ABSTRACTHepatitis C virus (HCV) glycoprotein E2 is considered a major target for generating neutralizing antibodies against HCV, primarily due to its role of engaging host entry factors, such as CD81, a key cell surface protein associated with HCV entry. Based on a series of biochemical analyses in combination with molecular docking, we present a description of a potential binding interface formed between the E2 protein and CD81. The virus side of this interface includes a hydrophobic helix motif comprised of residues W437LAGLF442, which encompasses the binding site of a neutralizing monoclonal antibody, mAb41. The helical conformation of this motif provides a structural framework for the positioning of residues F442 and Y443, serving as contact points for the interaction with CD81. The cell side of this interface likewise involves a surface-exposed hydrophobic helix, namely, the D-helix of CD81, which coincides with the binding site of 1D6, a monoclonal anti-CD81 antibody known to block HCV entry. Our illustration of this virus-host interface suggests an important role played by the W437LAGLF442helix of the E2 protein in the hydrophobic interaction with the D-helix of CD81, thereby facilitating our understanding of the mechanism for antibody-mediated neutralization of HCV.IMPORTANCECharacterization of the interface established between a virus and host cells can provide important information that may be used for the control of virus infections. The interface that enables hepatitis C virus (HCV) to infect human liver cells has not been well understood because of the number of cell surface proteins, factors, and conditions found to be associated with the infection process. Based on a series of biochemical analyses in combination with molecular docking, we present such an interface, consisting of two hydrophobic helical structures, from the HCV E2 surface glycoprotein and the CD81 protein, a major host cell receptor recognized by all HCV strains. Our study reveals the critical role played by hydrophobic interactions in the formation of this virus-host interface, thereby contributing to our understanding of the mechanism for antibody-mediated neutralization of HCV.

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In Vitro RNA Replication Directed by Replicase Complexes Isolated from the Subgenomic Replicon Cells of Hepatitis C Virus

Journal of Virology ◽

10.1128/jvi.77.3.2295-2300.2003 ◽

2003 ◽

Vol 77 (3) ◽

pp. 2295-2300 ◽

Cited By ~ 43

Author(s):

Vicky C. H. Lai ◽

Shannon Dempsey ◽

Johnson Y. N. Lau ◽

Zhi Hong ◽

Weidong Zhong

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Rna Synthesis ◽

Divalent Cations ◽

Hcv Rna ◽

Nonstructural Proteins ◽

Subgenomic Replicon ◽

Free System ◽

Potential Inhibitors

ABSTRACT Replication of hepatitis C virus (HCV) RNA in virus-infected cells is believed to be catalyzed by viral replicase complexes (RCs), which may consist of various virally encoded nonstructural proteins and host factors. In this study, we characterized the RC activity of a crude membrane fraction isolated from HCV subgenomic replicon cells. The RC preparation was able to use endogenous replicon RNA as a template to synthesize both single-stranded (ss) and double-stranded (ds) RNA products. Divalent cations (Mg2+ and Mn2+) showed different effects on RNA synthesis. Mg2+ ions stimulated the synthesis of ss RNA but had little effect on the synthesis of ds RNA. In contrast, Mn2+ ions enhanced primarily the synthesis of ds RNA. Interestingly, ss RNA could be synthesized under certain conditions in the absence of ds RNA, and vice versa, suggesting that the ss and ds RNA were derived either from different forms of replicative intermediates or from different RCs. Pulse-chase analysis showed that radioactivity incorporated into the ss RNA was chased into the ds RNA and other larger RNA species. This observation indicated that the newly synthesized ss RNA could serve as a template for a further round of RNA synthesis. Finally, 3′ deoxyribonucleoside triphosphates were able to inhibit RNA synthesis in this cell-free system, presumably through chain termination, with 3′ dGTP having the highest potency. Establishment of the replicase assay will facilitate the identification and evaluation of potential inhibitors that would act against the entire RC of HCV.

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Synthesis of some benzimidazole derivatives endowed with 1,2,3-triazole as potential inhibitors of hepatitis C virus

Acta Pharmaceutica ◽

10.1515/acph-2016-0014 ◽

2016 ◽

Vol 66 (2) ◽

pp. 219-231 ◽

Cited By ~ 7

Author(s):

Bahaa G. M. Youssif ◽

Yaseen A. M. Mohamed ◽

Mohammed T. A. Salim ◽

Fuyuhiko Inagaki ◽

Chisato Mukai ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Viable Cell ◽

Benzimidazole Derivatives ◽

Significant Activity ◽

B Virus ◽

Potential Inhibitors ◽

Derivatives Of ◽

Insight Into

Abstract New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.

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