Docking Studies of Pakistani HCV NS3 Helicase: A Possible Antiviral Drug Target

Abstract

The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) helicase is believed to be essential for viral replication and has become an attractive target for the development of antiviral drugs. The study of helicase is useful for elucidating its involvement in positive sense single-stranded RNA virus replication and to serve as templates for the design of novel antiviral drugs. In recent years, several models have been proposed on the conformational change leading to protein movement and RNA unwinding. Some compounds have been recently reported to inhibit the helicase and these include small molecules, RNA aptamers and antibodies. The current study is designed to help gain insights for the consideration of potential inhibitors for Pakistani HCV NS3 helicase protein. We have cloned, expressed and purified HCV NS3 helicase from Pakistani HCV serum samples and determined its 3D structure and employed it further in computational docking analysis to identify inhibitors against HCV genotype 3a (GT3a),including six antiviral key molecules such as quercetin, beta-carotene, resveratrol, catechins, lycopene and lutein. The conformation obtained after docking showed good hydrogen bond (HBond) interactions with best docking energy for quercetin and catechins followed by resveratrol and lutein. These anti-helicase key molecules will offer an alternative attraction to target the viral helicase, due to the current limitation with the interferon resistance treatment and presences of high rate of resistance in anti-protease inhibitor classes.

In-silico design and molecular docking evaluation of peptides derivatives from bacteriocins and porcine beta defensin-2 as inhibitors of Hepatitis E virus capsid protein

“…This diterpene interacts with both, the native and the mutated structures of the HCV NS3-4A protease, with a docking score of -15.1 kcal/mol, and this interaction was mediated mainly by the presence of hydrogen bonds between the ligand and S, A and H amino acids in the target protein [5]; in our study, the best interaction between subti1 and HEV capsid protein showed a docking score of -7.0 kcal/mol and was also mediated by the presence of A504 in chain A of the HEV capsid protein, forming two hydrogen bonds ( Table 2). In a similar way, bioflavonoids showed a promissory anti-HCV helicase activity, with high docking scores and with residues D and S as the main amino acids participating in the interaction [13]; these residues were also mediating the interaction of HEV capsid protein and the AVPs designed in our study, suggesting that D and S could be crucial for AVPs interactions ( Table 2). For HCV capsid protein a strongly interaction between naturalderived bioflavonoid has also been demonstrated; in this case, high docking scores according to Molegro Virtual Docker software were probably due to ten H-bonds involving three R residues [29], and in the same way, all the interactions between the six AVPs reported in this study involved R460 in both chains ( Table 2).…”

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].…”

Computational Molecular Docking and X-ray Crystallographic Studies of Catechins in New Drug Design Strategies

“…Among various compounds, including quercetin, catechins, resveratrol, and lutein, the former two compounds showed good hydrogen bond interactions with best docking energy. These anti-helicase molecules would offer a clue in the development of antiviral drugs [ 96 ].…”