Influenza viruses contain two major surface glycoproteins, hemagglutinin and neuraminidase, which are therapeutic targets for inhibiting influenza viruses from infecting host cell. Pandemic of H1N1/09 virus has been reported, and drug resistance was regarded as an important issue since 2009. Thus, the purpose of this research is to design novel potent dual inhibitors for the two surface glycoproteins on H1N1 virus. In this study, structure-based and ligand-based drug designs were performed to analyze interactions between target proteins and ligands, and molecular dynamics (MD) simulations were carried out to analyze the interaction of receptor-ligand complexes. Potent derivatives from structure-based design were ranked by sum of DockScore of two target proteins (H1 and N1) and were compared with Tamiflu (Oseltamivir) and Relenza (Zanamivir) to select the top 10 candidates. Among the scaffold of top 10 candidates, five key features were recognized for binding to H1 and N1. In quantitative structure-activity relationship models, these features were able to fit with their steric, electrostatic, hydrogen bond acceptor and donor fields. These fields were close to key residues of H1 and N1 binding site. Finally, 2-aminopyridinium group was noticed to play an important role in binding ability during 20ns MD simulations. From structure-based and ligand-based designs, we hope that we provided useful information for designing anti-viral compounds targeting H1 and N1, and we recommend the top 10 candidates from our experiments for further drug development testing.
