Virtual screening for oseltamivir-resistant a (H5N1) influenza neuraminidase from traditional Chinese medicine database: a combined molecular docking with molecular dynamics approach

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.

Keywords: Molecular docking; Molecular dynamic simulation; Oseltamivir-resistance; Traditional Chinese medicine database (TCMD); Virtual screening.

Figure 1

Docked poses of oseltamivir with wild (A, B and C) and mutant type NA (D, E and F).

Figure 2

Docked poses of neoglucobrassicin with wild (A, B and C) and mutant type NA (D, E and F).

Figure 3

The interaction of Oseltamivir (a) and Neoglucobrassicin (b) with wild type NA (PDB Code 2HU4).

Figure 4

The interaction of Oseltamivir (a) and Neoglucobrassicin (b) with mutant type NA (PDB Code 3CL0).

Figure 5

Backbone root mean square deviations correspond to wild-oseltamivir (black), mutant-oseltamivir (red) and mutant- neoglucobrassicin (green) along the MD simulation at 300k.

Figure 6

Root mean square deviations correspond to ligand in NA-ligand complexes: wild-oseltamivir (black), mutant-oseltamivir (red) and mutant- neoglucobrassicin (green) along the MD simulation at 300k.

Figure 7

Osiris property explorer showing drug likeness properties of Neoglucobrassicin.