Insights from modeling the 3D structure of H5N1 influenza virus neuraminidase and its binding interactions with ligands

• Published in: Biochemical and biophysical research communications 2006-06, Vol.344 (3), p.1048-1055
• Main Authors: Wei, Dong-Qing, Du, Qi-Shi, Sun, Hao, Chou, Kuo-Chen
• Format: Article
• Language: English
• Subjects: Acetamides - chemistry; Avian influenza; Binding Sites; Bird flu; Computer Simulation; DANA; Drug-resistance; Enzyme Activation; Guanidines - chemistry; H5N1; Hydrophilic pocket; Influenza A Virus, H5N1 Subtype - enzymology; Influenza virus; Lipophilic pocket; Models, Chemical; Models, Molecular; N-Acetylneuraminic Acid - analogs & derivatives; N-Acetylneuraminic Acid - chemistry; Neuraminidase; Neuraminidase - chemistry; Oseltamivir; Protein Binding; Protein Conformation; Pyrans - chemistry; Sequence Analysis, Protein - methods; Sialic Acids - chemistry; Structural bioinformatics; Structure-Activity Relationship; Structure–active relationship; Zanamivir
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2006.03.210

The highly pathogenic H5N1 influenza virus, which is rapidly mutating and becoming increasingly drug-resistant, was investigated by means of structure–activity relationship between NA (neuraminidase) and three inhibitors, i.e., DANA (2,3-didehydro-2-deoxy- N-acetylneuraminic acid), zanamivir, and oseltamivir. A homology model of the H5N1-NA from the highly pathogenic chicken H5N1 A viruses isolated during the 2003–2004 influenza outbreaks in Japan was built based on the crystal structure of N9-NA complexed with DANA (PDB code: 1F8B). It was found that the traditional constituent residues around the active site of NA family are highly conserved in the H5N1-NA. However, a partially lipophilic pocket composed by Ala248 and Thr249 in N9-NA becomes a hydrophilic pocket because the two residues in the H5N1-NA are replaced by hydrophilic residues Ser227 and Asn228, respectively. On the other hand, two hydrophilic residues Asn347 and Asn348 in the N9-NA are replaced by two lipophilic residues Ala323 and Tyr324 in the H5N1-NA, respectively, leading to the formation of a new lipophilic pocket. This kind of subtle variation not only destroys the original lipophilic environment but also changes the complement interaction between the H5N1-NA and DANA. Such a finding might provide insights into the secret why some of H5N1 strains bear high resistance for existing NA inhibitors, and stimulate new strategies for designing new drugs against these viruses.