A STRUCTURAL AND ENERGETICS ANALYSIS OF THE BINDING OF A SERIES OF N-ACETYLNEURAMINIC-ACID-BASED INHIBITORS TO INFLUENZA-VIRUS SIALIDASE

A molecular dynamics/energy-minimisation protocol has been used to ana lyse the structural and energetic effects of functional group substitu tion on the binding of a series of C4-modified 2-deoxy-2,3-didehydro-N -acetylneuraminic acid inhibitors to influenza virus sialidase. Based on the crystal structure of sialidase, a conformational searching prot ocol, incorporating multiple randomisation steps in a molecular dynami cs simulation was used to generate a range of minimum-energy structure s. The calculations were useful for predicting the number, location, a nd orientation of structural water molecules within protein-ligand com plexes. Relative binding energies were calculated for the series of co mplexes using several empirical molecular modelling approaches. Energi es were computed using molecular-mechanics-derived interactions as the sum of pairwise atomic nonbonded energies, and in a more rigorous man ner including solvation effects as the change in total electrostatic e nergy of complexation, using a continuum-electrostatics (CE) approach. The CE approach exhibited the superior correlation with observed affi nities. Both methods showed definite trends in observed and calculated binding affinities; in both cases inhibitors with a positively charge d C4 substituent formed the tightest binding to the enzyme, as observe d experimentally.