With the hemagglutinin, the neuraminidase dominate the surface of the influenza virus and form the main targets for neutralizing antibodies . The functions of neuraminidase, as well as the hemagglutinin, involve interaction with the sialic acid bound to sugar residues expressed by glycoproteins or glycolipids at the cell surface . The neuraminidase cleaves sialic acids in order to prevents virion aggregation (sialylation from cell host), and avoid the virus binding back to the dying host via the The catalytic site is present on the surface, and it is characterized by a large cavity with an unusual large number of charged residues 150 . The catalytic site is highly conserved with eight residues that interact directly with sialic acids (Arg118, Asp151, Arg152, Arg224, Glu276, Arg292, Arg371 and Tyr406) and with 11 other residues part of the outer shell. Mutations in the catalytic site are at the origin of the inhibitor resistance observed in some influenza strains . For example in H1N1, the most common mutations found are E119D/G, I223R, S247G/R and H275Y. Combinations of some those mutations confer resistance against all approved neuraminidase inhibitors (Zanamivir, Oseltamivir (Tamiflu), Peramivir and Laninamivir). In the hope to find new neuraminidase inhibitors against those mutants, an accurate description of water molecules is necessary, largely due to the presence of charged residues, to properly describe proteininhibitor interactions.