Design of multi-binding-site inhibitors, ligand efficiency, and consensus screening of avian influenza H5N1 wild-type neuraminidase and of the oseltamivir-resistant H274Y variant.
The binding sites of wild-type avian influenza A H5N1 neuraminidase, as well as those of the Tamiflu (oseltamivir)-resistant H274Y variant, were explored computationally to design inhibitors that target simultaneously several adjacent binding sites of the open conformation of the virus protein. The compounds with the best computed free energies of binding, in agreement by two docking methods, consensus scoring, and ligand efficiency values, suggest that mimicking a polysaccharide, beta-lactam, and other structures, including known drugs, could be routes for multibinding site inhibitor design. This new virtual screening method based on consensus scoring and ligand efficiency indices is introduced, which allows the combination of pharmacodynamic and pharmacokinetic properties into unique measures.
García-Sosa
Alfonso T
AT
Institute of Chemistry, University of Tartu, Jakobi 2-319, Tartu, Estonia. t.alfonso@gmail.com
Sild
Sulev
S
Maran
Uko
U
D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D019281:Dimerization; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology* / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D053139:Oseltamivir / Q000494:pharmacology*; D019151:Peptide Library; D011487:Protein Conformation; D012984:Software
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D019151:Peptide Library; D053139:Oseltamivir; D009439:Neuraminidase