Abstract
The neuraminidase (NA) of the influenza virus is the target of antiviral drug, oseltamivir. Recently, cases are reported that Influenza virus becoming resistant to oseltamivir, necessitating the development of new long-acting antiviral compounds. Most importantly, H274Y mutation in neuraminidase exhibits high levels of resistance to oseltamivir. In this report, a novel class of lead molecule with potential NA inhibitory activity was found from the traditional Chinese medicine database (TCMD) using virtual screening approach. Initially ADME properties of the lead compounds were analyzed with respect to the Lipinski rule of five. Subsequently, the data reduction was carried out by employing molecular docking study. Final validation was done by means of molecular dynamic simulations. The toxicity profiles for the screened compound were also analyzed. The result indicates that neoglucobrassicin (a compound derived from TCMD) become a promising lead compound and be effective in treating oseltamivir-resistant influenza virus strains.
Highlights
Avian influenza A (H5N1) virus is highly pathogenic which leads to high mortality rate in humans
In particular H274Y, the principal mutation isolated in association with oseltamivir treatment that is specific to the N1 group (Yen et al 2007) and that has recently been shown to be present in substantial numbers of H5N1 viruses isolated from humans (Uyeki 2009)
The results showed that 4 molecules have zero violations of the Rule of 5 which suggest that these molecules likely to have good bioavailability (Table 1)
Summary
Avian influenza A (H5N1) virus is highly pathogenic which leads to high mortality rate in humans. Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and it contains two subunits which have different functions. HA2 mediates fusion of membrane and viral entry, while HA1 is involved in Neuraminidase (NA) inhibition is a pivotal step in restricting the spread of influenza virus infection in the host. Oseltamivir is the first line antiviral drug used for the treatment against influenza and it is an active influenza neuraminidase inhibitor which is recommended for treating and preventing influenza virus infection. There have been reports of oseltamivir-resistant mutant selection in vitro and from infected humans. In particular H274Y, the principal mutation isolated in association with oseltamivir treatment that is specific to the N1 group (Yen et al 2007) and that has recently been shown to be present in substantial numbers of H5N1 viruses isolated from humans (Uyeki 2009). The basic goal of the virtual screening is the reduction of the enormous virtual chemical space of small organic molecules, to synthesize and/or screen against a specific target protein, to a manageable number of the compound that inhibit a highest chance to lead to a drug candidate
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