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.