Potential tripeptides against the tyrosine kinase domain of human epidermal growth factor receptor (HER) 2 through computational and kinase assay approaches

Abstract

An abnormal activation of human epidermal growth factor receptor (HER) 2 has been found to associate with several types of human cancer, and thus the protein is a prominent target for cancer therapy. Although several small chemical molecules targeting the tyrosine kinase (TK) of HER family have been identified, the development of a new class of inhibitors, i.e., small peptides inhibiting the function of tyrosine kinase is still promising. Here, we screened 8000 tripeptides for candidate potential inhibitors against HER2-TK using molecular docking. Our in vitro kinase assays showed that the candidate tripeptides had more than 50% relative inhibition to HER2-TK. Even though these tripeptides had much lower inhibitory activity than that of the drug Lapatinib, the tripeptides WWW exhibited high inhibitory activity with the IC₅₀ of ≈283 μM, while FYW showed lower activity with the IC₅₀ of ≈1723 μM. The relative binding free energies calculated by MM/PBSA method were comparable to the inhibition experiment in that Lapatinib binding was ≈-139 kJ/mol whereas the binding of WWW and FYW was ≈-112 kJ/mol and ≈-81 kJ/mol, respectively. Energy calculation also indicated that the HER2-TK/inhibitor interactions were dominated by van der Waals over electrostatic contributions. In addition, molecular interaction analyses revealed that several interacting residues with more negative binding free energy could mostly contribute the hydrophobic interaction. Therefore, we suggested preferable interactions for further development of potential tripeptides as a new anticancer peptide targeting HER2-TK.

Keywords: HER2-TK; MM/PBSA; Molecular docking; Molecular dynamics simulation; Tripeptide; Tyrosine kinase inhibitor.