title: Understanding the cross-resistance of oseltamivir to H1N1 and H5N1 influenza A neuraminidase mutations using multidimensional computational analyses.
abstract: This study embarks on a comprehensive description of the conformational contributions to resistance of neuraminidase (N1) in H1N1 and H5N1 to oseltamivir, using comparative multiple molecular dynamic simulations. The available data with regard to elucidation of the mechanism of resistance as a result of mutations in H1N1 and H5N1 neuraminidases is not well established. Enhanced post-dynamic analysis, such as principal component analysis, solvent accessible surface area, free binding energy calculations, and radius of gyration were performed to gain a precise insight into the binding mode and origin of resistance of oseltamivir in H1N1 and H5N1 mutants. Three significant features reflecting resistance in the presence of mutations H274Y and I222K, of the protein complexed with the inhibitor are: reduced flexibility of the α-carbon backbone; an improved ΔEele of ~15 (kcal/mol) for H1N1 coupled with an increase in ΔGsol (~13 kcal/mol) from wild-type to mutation; a low binding affinity in comparison with the wild-type of ~2 (kcal/mol) and ~7 (kcal/mol) with respect to each mutation for the H5N1 systems; and reduced hydrophobicity of the overall surface structure due to an impaired hydrogen bonding network. We believe the results of this study will ultimately provide a useful insight into the structural landscape of neuraminidase-associated binding of oseltamivir. Furthermore, the results can be used in the design and development of potent inhibitors of neuraminidases.
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, South Africa.
authors.forename: Ashona
authors.initials: A
authors.lastname: Singh
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, South Africa.
authors.forename: Mahmoud E
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005838:Genotype; D006860:Hydrogen Bonding; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053139:Oseltamivir / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D025341:Principal Component Analysis; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase
keywords: binding free energy; molecular dynamics; mutation; neuraminidase; resistance