Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, CP: 11340, Mexico City, Mexico.
J Mol Model. 2021 Mar 8;27(4):105. doi: 10.1007/s00894-021-04720-5.
Experimental and theoretical studies have provided structural information regarding the shift from inactive to active EGFR, throughout which both conformations are linked via binding to specific tyrosine kinase inhibitors. For HER2, an intermediate active-inactive receptor conformation is present in the PDB, which has been co-crystallized with tak-285. The affinity of HER2 in monomeric state to tak-285 has been previously reported. However, the lack of structural knowledge of HER2 limits our capacity to understand whether tak-285, or other known HER2 inhibitors, selectively bind active, inactive, or intermediate forms of HER2. To elucidate mechanisms by which tak-285 binds to HER2, we first obtained information regarding the structural features of the active state of HER2 via microsecond MD simulations from the crystallized intermediate structure previously determined. Based on these HER2 conformers, together with the inactive HER2 conformer obtained in a previous study, we used docking and MD simulations coupled to MMGBSA approach to assess binding of tak-285 and lapatinib, known HER2/EGFR dual inhibitors, to HER2. Structural and energetic studies revealed that tak-285 binds with a greater affinity than lapatinib to active and intermediate active-inactive forms of HER2. This is in accordance with experimental findings that showed the tak-285 inhibitor has increased activity relative to lapatinib in breast cancer cell lines.
实验和理论研究为从非活性 EGFR 向活性 EGFR 的转变提供了结构信息，在这一过程中，两种构象都通过与特定的酪氨酸激酶抑制剂结合而相互关联。对于 HER2，PDB 中存在一个中间体活性-非活性受体构象，该构象已与 tak-285 共结晶。HER2 在单体状态下与 tak-285 的亲和力先前已有报道。然而，由于缺乏 HER2 的结构知识，我们无法理解 tak-285 或其他已知的 HER2 抑制剂是否选择性地结合活性、非活性或中间体形式的 HER2。为了阐明 tak-285 与 HER2 结合的机制，我们首先通过先前确定的结晶中间体结构的微秒 MD 模拟获得了关于 HER2 活性状态的结构特征信息。基于这些 HER2 构象，以及先前研究中获得的非活性 HER2 构象，我们使用对接和 MD 模拟与 MMGBSA 方法相结合，评估了已知的 HER2/EGFR 双重抑制剂 tak-285 和 lapatinib 与 HER2 的结合。结构和能量研究表明，tak-285 与 lapatinib 相比，与 HER2 的活性和中间体活性-非活性形式的结合亲和力更强。这与实验结果一致，表明在乳腺癌细胞系中，与 lapatinib 相比，tak-285 抑制剂的活性更高。
