title: Molecular dynamics and free energy analysis of neuraminidase-ligand interactions.
abstract: We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidase binding free energy. Based on the N-DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson-Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance-dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four-substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004735:Energy Transfer; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008956:Models, Chemical; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009975:Orthomyxoviridae / Q000201:enzymology*; D055672:Static Electricity
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid