Binding mechanism of H5N1 influenza virus neuraminidase with ligands and its implication for drug design.
To simulate new strategies for designing effective drugs against bird flu, we have carried out extensive studies by using various computer-aided drug design tools. Molecule AG7088 was first docked to the active site of H5N1 avian influenza neuraminidase (PBD code: 2HTY). The results thus obtained were compared with those by docking zanamivir (Relenza) and oseltamivir (Tamiflu) to the same receptor, respectively. It has been found that the compound AG7088 has better binding energy than zanamivir and oseltamivir. Thus, it was adopted as a template to perform the similarity search of 392,698 druggable compounds in order to find the leading candidates for the next step of modeling studies. Nine analogs of AG7088 were singled out through a series of docking studies. Finally, the molecular dynamics simulation technique was utilized to investigate into the binding interactions between the H5N1 receptor and the nine analogs, with a focus on the binding pocket, intermolecular surfaces and hydrogen bonds. This study may be used as a guide for mutagenesis studies for designing new inhibitors against H5N1.
Gong
Ke
K
College of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai, China.
Li
Lin
L
Wang
Jing-Fang
JF
Cheng
Feng
F
Wei
Dong-Qing
DQ
Chou
Kuo-Chen
KC
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000201:enzymology*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D009439:Neuraminidase