Design, Synthesis, and Docking Studies of Peptidomimetics Based on HER2–Herceptin Binding Site with Potential Antiproliferative Activity Against Breast Cancer Cell lines

Abstract

Epidermal growth factor receptor (EGFR) kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2-herceptin complex, several peptidomimetics (HERP5, 6 & 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. Autodock software was used to dock the different analogs of HERP5 and HERP7 with HER2 protein extracellular domain. A total of 53 compounds were docked to HER2 protein, and their binding modes were analyzed in terms of docking energy, hydrogen bonding, and hydrophobic interactions. Compounds that exhibited low energy docked structures were chosen for chemical synthesis and biological activity. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC 50 values of 0.396 μM and 0.143 μM, respectively, against SKBR-3 cell lines (breast cancer cell lines) that overexpress HER2 protein.Keywords breast cancer; docking; HER2; MTT assay; SKBR-3 cell line; virtual screening Human tumors express high levels of growth factors and their receptors. Epidermal growth factor receptors (EGFR) are the best-studied growth factor receptor family (1). This family consists of four homologous receptors, namely, epidermal growth factor receptor 1 (also called EGFR, ErbB1) or human epidermal growth factor receptor 1 (HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (2-7). In normal cells, activation of this receptor tyrosine kinase family triggers signaling pathways that control normal cell growth, differentiation, and motility. It is well established that binding of extracellular ligands such as epidermal growth factor (EGF) and transforming growth factor α (TGFα) to the extracellular ligand binding domain of EGFR results in receptor homo-heterodimerization, Supplementary materialThe following supplementary material is available for this article. HPLC, mass spectra, NMR data for compound HERP5 and HR-MS data for HERP5, 6 and 7. NIH Public Access Author ManuscriptChem Biol Drug Des. Author manuscript; available in PMC 2010 September 1. Results and Discussion Design strategyDomains II and IV of the HER2 extracellular region play major roles in multimerization of HERs and the downstream signaling that leads to cell growth (5). The crystal structure of HER2-herceptin complex indicates that the binding site on HER2 domain IV has a pocketlike structure homologous to that of domain II of other HERs (4). This pocket accommodates binding of small peptide/peptidomimetic molecules, which can modulate HER2-mediated signaling. Analysis of 3D structures and resultan...

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