For the development of new targeted drug delivery vectors and molecular imaging reagents, it is essential to find the appropriate ligand that is both safe and efficient. Ligands against EGFR are highly sought after since it is highly expressed on many kinds of tumor cells and considered as a good target in cancer therapy. A new binding site based on EGFR 3D structure was proposed and DTP-Plated small molecule database was screened using the DOCK program. The selected molecules were further evaluated for their in vitro binding capacity using the BIAcore technique. It was shown that the molecule NSC51186 may be a novel small molecule targeting ligand for EGFR. Further studies are warranted to investigate its potential in targeted drug delivery and gene delivery, as well as molecular diagnosis applications.