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

Publication date: Available online 4 February 2020Source: Journal of Molecular Graphics and ModellingAuthor(s): Supaphorn Seetaha, Bundit Boonyarit, Sissades Tongsima, Napat Songtawee, Kiattawee ChoowongkomonAbstractAn 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 8,000 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 ≈1,723 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 electro...

Source: Journal of Molecular Graphics and Modelling - February 4, 2020 Category: Molecular Biology Source Type: research