Molecular docking approach helps us in identifying best binding ligands with the protein target and helps in exploring new small molecular leads from natural sources with higher binding affinities. These lead molecules enter into the higher phases of drug development and may end up as a good drug candidate. The protein ligand interactions were carried out using Schrodinger (GLIDE) commercial software. The target protein, the crystal structure of extracellular domain of human HER2, complexed with Herceptin Fab, was considered for this analysis. The Herceptin Fab domain was removed for the docking of commercial drugs with HER2. The ligands considered are: the commercial drugs, Afinitor, Halaven, Ixabipilone, Lapatinib, Letrozole, Palbociclib, Raloxifene and Tamoxifen and the natural compounds Oleic acid and Stigmasterol isolated from marine sponge Aurora globostellata. In this study, XP Docking procedure was used. It ranks the best conformations based on the ligand binding to the receptor molecules.