Dynamic behavior of avian influenza A virus neuraminidase subtype H5N1 in complex with oseltamivir, zanamivir, peramivir, and their phosphonate analogues.

The outbreak of avian influenza A subtype H5N1 virus has raised a global concern for both animal as well as human health. Recently, drug resistance in H5N1 infections has been widely reported due to neuraminidase mutations. Consequently, the understanding of inhibitor-neuraminidase interactions at the molecular level represents the main goal of our study. Molecular dynamics simulations were carried out for the neuraminidase N1 in complex with six inhibitors--oseltamivir, zanamivir, peramivir, and their phosphonate analogues. Molecular dynamics trajectories were extensively analyzed in terms of important interactions between inhibitors and the enzyme target. Results show that open and closed forms (defined by the relative position of the flexible 150-loop) of neuraminidase N1 interchange during the course of 20 ns molecular dynamics simulation of the protein-inhibitor complexes. Reported free energies of closing indicate that the carboxylate inhibitors prefer the closed form more than their phosphonate analogues. This can be understood in view of the negative total charge (-1 e0) of the phosphonate inhibitors, which repels the Asp151 residue of the loop away from the inhibitor and drives the complex into the open form. Obtained results constitute new valuable information to assist further drug development of inhibitors against the H5N1 avian influenza A virus and could also inspire similar studies for other systems of the influenza family such as the 2009 influenza A (H1N1) virus.