Computational design of novel, high-affinity neuraminidase inhibitors for H5N1 avian influenza virus.

To propose more effective inhibitors for neuraminidase subtype N1, four potential inhibitors were molecularly designed by substitution at the C(3) position of oseltamivir to give additional interaction with the 150-cavity, since a new cavity known as the '150-cavity' adjacent to the well-known active site has been found in the neuraminidase subtype N1. We calculated the binding free energy of both oseltamivir and the newly designed inhibitors for subtype N1, using molecular dynamics simulations, to predict their drug effectiveness. When the drug effectiveness of four potential inhibitors is compared with that of oseltamivir, we discovered a highly potent neuraminidase inhibitor, which exhibited much higher binding affinity to subtype N1 than oseltamivir (-17.77 vs. -8.06 kcal/mol).