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.

已经发现人类表皮生长因子受体（HER）2的异常激活与几种类型的人类癌症有关，因此该蛋白质是癌症治疗的重要靶标。尽管已经鉴定了靶向HER家族的酪氨酸激酶（TK）的几种小化学分子，但是新型抑制剂的开发，即抑制酪氨酸激酶功能的小肽仍然有希望。在这里，我们使用分子对接筛选了8000种三肽作为HER2-TK潜在抑制剂的候选药物。我们的体外激酶测定表明候选三肽对HER2-TK的相对抑制率超过50％。尽管这些三肽具有很低的抑制作用比药物拉帕替尼，三肽WWW表现出较高的抑制活性用IC ₅₀ ≈283微米，而FYW显示出与IC低活动₅₀≈1723μM MM / PBSA方法计算的相对结合自由能与抑制实验相当，因为拉帕替尼的结合约为≈-139kJ / mol，而WWW和FYW的结合约为≈-112kJ / mol和≈-81kJ / mol，分别。能量计算还表明，HER2-TK /抑制剂之间的相互作用受范德华斯作用超过静电作用。此外，分子相互作用分析表明，具有更多负结合自由能的几个相互作用残基可主要促进疏水相互作用。因此，我们建议潜在相互作用的三肽作为靶向HER2-TK的新抗癌肽的进一步开发的优选相互作用。