Avian Flu Grid

The avian influenza virus type A, especially subtype H5N1, is becoming the world’s largest pandemic threat due to its high virulence and lethality rate in birds, quickly expanding host reservoir, and high rate of mutations. The two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA) of influenza virus play important roles in the interactions with cellular receptors containing terminal N-acetylneuraminic acid (Neu5Ac, or NANA) moieties, aka, sialic acids. The approved anti-influenza drugs, oseltamivir and zanamivir, inhibit H5N1 infection by targeting the NA active site, thereby blocking the release of newly formed viral particles. However, research has shown that antigenic drift may give rise to new strains that are resistant to existing NA inhibitors and antigenic shift could give rise to new virulent subtypes of the flu virus.
Thus, it is crucial to design novel HA- and NA-targeted inhibitors, which can be used in combination for optimal prophylaxis and treatment. The Relaxed Complex (RC) scheme and Molecular Dynamics (MD) simulations have been applied on the two target proteins to capture key protein dynamics information and accounting for receptor flexibility. Research is under way to take advantage of novel loop flexibilities and changing cavity shapes adjacent to NA active site to discover novel NA inhibitors that may work in a way similar to the HIV integrase inhibitor, raltegravir, inspired by the RC/MD simulation procedures. Further investigation involves statistical cluster analysis for rational selection of representative HA/NA protein structure snapshots, which are used in the virtual screening with synthetic and natural compound libraries. Finally, the binding energies of the high scoring hits are re-scored using Molecular Mechanics-Poisson Bolzmann Surface Area (MM-PBSA) method before experimental validation and subsequent lead optimization.