title: A structural and energetics analysis of the binding of a series of N-acetylneuraminic-acid-based inhibitors to influenza virus sialidase.
abstract: A molecular dynamics/energy-minimisation protocol has been used to analyse the structural and energetic effects of functional group substitution 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 protocol, incorporating multiple randomisation steps in a molecular dynamics simulation was used to generate a range of minimum-energy structures. The calculations were useful for predicting the number, location, and orientation of structural water molecules within protein-ligand complexes. Relative binding energies were calculated for the series of complexes using several empirical molecular modelling approaches. Energies were computed using molecular-mechanics-derived interactions as the sum of pairwise atomic nonbonded energies, and in a more rigorous manner including solvation effects as the change in total electrostatic energy of complexation, using a continuum-electrostatics (CE) approach. The CE approach exhibited the superior correlation with observed affinities. Both methods showed definite trends in observed and calculated binding affinities; in both cases inhibitors with a positively charged C4 substituent formed the tightest binding to the enzyme, as observed experimentally.
authors.affiliation: Department of Medical Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Australia.
authors.forename: N R
authors.initials: NR
authors.lastname: Taylor
authors.forename: M
authors.initials: M
authors.lastname: von Itzstein
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000201:enzymology*; D011485:Protein Binding; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D014764:Viral Proteins; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid