Novel hemagglutinin inhibitors for H1N1 influenza virus screening from TCM database

Abstract

The emergence of Tamiflu (oseltamivir)-resistant viral strains in pandemic of H1N1/09 influenza virus has raised global awareness of anti-viral drug resistant issue. There is an urgent demand for developing new anti-influenza compound. The purpose of this research is to design novel haemagglutinin (HA) inhibitor for inhibiting viral entry into the host cell. We performed structure-based drug design to analyse interactions between the potent inhibitor and HA. A traditional Chinese medicine (TCM) database was used for in silico screening process. The docked TCM constituents were input into de novo evolution to generate derivatives. Selected derivatives were then docked back to HA binding site. We identify four key features from top 10 docked derivatives' binding conformations and structure scaffolds. The addition of 2-aminopyridinium group has the greatest influence in the binding ability of TCM derivatives and is, therefore, suggested to be the key point in designing HA inhibitors.

Keywords:

• H1N1
• Tamiflu
• docking
• structure-based drug design
• traditional Chinese medicine

Acknowledgements

The research was supported by grants from the National Science Council of Taiwan (NSC 99-2221-E-039-013-), China Medical University (CMU98-TCM, CMU99-S-02) and Asia University (CMU98-ASIA-09). This study was also supported in part by the Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH99-TD-B-111-004) and the Taiwan Department of Health Cancer Research Center of Excellence (DOH99-TD-C-111-005). We are grateful to the National Center of High-performance Computing for computer time and facilities.

Notes

Both authors contributed equally to this work.