How does each substituent functional group of oseltamivir lose its activity against virulent H5N1 influenza mutants?
| Autor: | Pathumwadee Intharathep, Pornthep Sompornpisut, Thanyarat Udommaneethanakit, Thanyada Rungrotmongkol, Maturos Malaisree, Nadtanet Nunthaboot, Supot Hannongbua |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Oseltamivir
Stereochemistry Mutant Molecular Conformation Biophysics Substituent Virulence medicine.disease_cause Antiviral Agents Biochemistry chemistry.chemical_compound Hydrogen network Influenza A Virus H1N1 Subtype Drug Resistance Viral medicine Influenza A virus Humans Influenza A Virus H5N1 Subtype Influenza A Virus H3N2 Subtype Organic Chemistry Intermolecular force virus diseases Influenza A virus subtype H5N1 Amino Acid Substitution chemistry Mutation |
| Zdroj: | Biophysical Chemistry. 145:29-36 |
| ISSN: | 0301-4622 |
| DOI: | 10.1016/j.bpc.2009.08.006 |
| Popis: | To reveal the source of oseltamivir-resistance in influenza (A/H5N1) mutants, the drug-target interactions at each functional group were investigated using MD/LIE simulations. Oseltamivir in the H274Y mutation primarily loses the electrostatic and the vdW interaction energies at the -NH(3)(+) and -OCHEt(2) moieties corresponding to the weakened hydrogen-bonds and changed distances to N1 residues. Differentially, the N294S mutation showed small changes of binding energies and intermolecular interactions. Interestingly, the presence of different conformations of E276 positioned between the -OCHEt(2) group and the mutated residue is likely to play an important role in oseltamivir-resistant identification. In the H274Y mutant, it moves towards the -OCHEt(2) group leading to a reduction in hydrophobicity and pocket size, whilst in the N294S mutant it acts as the hydrogen network center bridging with R224 and the mutated residue S294. The molecular details have answered a question of how the H274Y and N294S mutations confer the high- and medium-level of oseltamivir-resistance to H5N1. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect