Understanding of known drug‐target interactions in the catalytic pocket of neuraminidase subtype N1

To provide detailed information and insight into the drug‐target interaction, structure, solvation, and dynamic and thermodynamic properties, the three known‐neuraminidase inhibitors—oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV)—embedded in the catalytic site of neuraminidase (NA) subtype N1 were studied using molecular dynamics simulations. In terms of ligand conformation, there were major differences in the structures of the guanidinium and the bulky groups. The atoms of the guanidinium group of PRV were observed to form many more hydrogen bonds with the surrounded residues and were much less solvated by water molecules, in comparison with the other two inhibitors. Consequently, D151 lying on the 150‐loop (residues 147–152) of group‐1 neuraminidase (N1, N4, N5, and N8) was considerably shifted to form direct hydrogen bonds with the OH group of the PRV, which was located rather far from the 150‐loop. For the bulky group, direct hydrogen bonds were detected only between the hydrophilic side chain of ZNV and residues R224, E276, and E277 of N1 with rather weak binding, 20–70% occupation. This is not the case for OTV and PRV, in which flexibility and steric effects due to the hydrophobic side chain lead to the rearrangement of the surrounded residues, that is, the negatively charged side chain of E276 was shifted and rotated to form hydrogen bonds with the positively charged moiety of R224. Taking into account all the ligand‐enzyme interaction data, the gas phase MM interaction energy of −282.2 kcal/mol as well as the binding free energy (ΔGbinding) of −227.4 kcal/mol for the PRV‐N1 are significantly lower than those of the other inhibitors. The ordering of ΔGbinding of PRV < ZNV < OTV agrees well with the ordering of experimental IC50 value. Proteins 2008. © 2008 Wiley‐Liss, Inc.