Malfunction or overexpression of ErbB receptors (epidermal growth factor receptors) is associated with occurrence and severity of several types of cancer. Initiation of signal cascades by ErbB2 (also known as human epidermal growth factor receptor 2/neu) in breast cancer has been blocked by monoclonal antibodies such as Trastuzumab (Herceptin), which interact with the extracellular domain of human epidermal growth factor receptor 2. Due to some disadvantages of monoclonal antibodies, a new approach in blocking human epidermal growth factor receptor 2 dimerization and activation is designing peptidomimetic ligands based on human epidermal growth factor receptor 2-Trastuzumab interaction model. Growth of human epidermal growth factor receptor 2+ SK-BR3 cells could be specifically inhibited by peptidomimetic herceptin-based peptidomimetic 5. In this study, herceptin-based peptidomimetic 5 was used as a benchmark peptidomimetic compound to perform a ligand-based virtual screening followed by structure-based screening by applying the molecular docking approach. The study aimed to explore more potent peptidomimetic molecules against extracellular part of human epidermal growth factor receptor 2. Our results showed that the newly designed peptidomimetic herceptin-based peptidomimetic n33B in comparison with herceptin-based peptidomimetic 5 binds more tightly to the extracellular domain of human epidermal growth factor receptor 2. Mechanistic aspects of herceptin-based peptidomimetic n33B interaction with human epidermal growth factor receptor 2 were more investigated through 20-ns molecular dynamic simulations. Additionally, a quantitative structure–activity relationships study was performed to develop a model for identification of structural determinants in herceptin-based peptidomimetic 5-based peptidomimetics.