Abnormalities in the expression levels of EGFR/HER2 are found in many different types of human cancer; therefore, the design of dual inhibitors of EGFR/HER2 is a recognized anti-cancer strategy. Some lapatinib derivatives have been previously synthesized by modification at the methylsulfonylethylaminomethylfuryl group and biologically evaluated, demonstrating that the 2i compound shows potent inhibitory activity against EGFR/HER2-overexpressing cancer cells. In the present study, we explored the structural and energetic features that guide the molecular recognition of 2i using various EGFR/HER2 states. Molecular dynamics (MD) simulation with an MMPB(GB)SA approach was used to generate the inactive EGFR/HER2-ligand complexes. Our results corroborate that slight modification of lapatinib contributes to an increase in the affinity of the 2i compound for inactive EGFR/HER2 as compared with lapatinib compound, which is in accordance with experimental results. Comparison with previous results reveals that lapatinib and its derivative bind more strongly to the inactive than the intermediate active-inactive HER2 state. Principal component analysis allowed the observation that coupling of 2i to EGFR/HER2 is linked to a reduction in the conformational mobility, which may also contribute to the improvement in affinity observed for this compound as compared with lapatinib.

中文翻译：

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剖析双拉帕替尼衍生物对EGFR / HER2的分子识别。

在许多不同类型的人类癌症中发现EGFR / HER2表达水平异常。因此，EGFR / HER2双重抑制剂的设计是公认的抗癌策略。某些拉帕替尼衍生物先前已通过在甲基磺酰基乙基氨基甲基呋喃基上的修饰进行合成，并进行了生物学评估，证明2i化合物对过表达EGFR / HER2的癌细胞显示出有效的抑制活性。在本研究中，我们探索了使用各种EGFR / HER2状态指导2i分子识别的结构和能量特征。使用MMPB（GB）SA方法进行的分子动力学（MD）模拟用于生成非活性EGFR / HER2-配体复合物。我们的结果证实，与拉帕替尼化合物相比，拉帕替尼的轻微修饰有助于2i化合物对非活性EGFR / HER2的亲和力增加，这与实验结果一致。与先前结果的比较表明，拉帕替尼及其衍生物比中间活性-非活性HER2状态更牢固地与非活性结合。主成分分析允许观察到2i与EGFR / HER2的偶联与构象迁移率的降低有关，与拉帕替尼相比，这也可能有助于改善该化合物的亲和力。与先前结果的比较表明，拉帕替尼及其衍生物比中间活性-非活性HER2状态更牢固地与非活性结合。主成分分析允许观察到2i与EGFR / HER2的偶联与构象迁移率的降低有关，与拉帕替尼相比，这也可能有助于改善该化合物的亲和力。与先前结果的比较表明，拉帕替尼及其衍生物比中间活性-非活性HER2状态更牢固地与非活性结合。主成分分析允许观察到2i与EGFR / HER2的偶联与构象迁移率的降低有关，与拉帕替尼相比，这也可能有助于改善该化合物的亲和力。