Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México, Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico City CP: 11340, Mexico.
Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México, Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico City CP: 11340, Mexico.
Int J Biol Macromol. 2018 May;111:569-586. doi: 10.1016/j.ijbiomac.2017.12.162. Epub 2018 Jan 9.
Activation of EGFR starts by ligand binding at the extracellular domain which results in homo and heterodimerization, leading to phosphorylation, activation of downstream signaling pathways which upregulate expression of genes, proliferation and angiogenesis. Abnormalities in the expression of EGFR play a critical role in the development of different types of cancer. HER2 is the preferred heterodimerization partner for EGFR; this biological characteristic together with the high percentage of structural homology has been exploited in the design of dual synthetic inhibitors against EGFR/HER2. Herein we combined structural data and molecular dynamics (MD) simulations coupled to an MMGBSA approach to provide insight into the binding mechanism between two dual synthetics (lapatinib and TAK-285) and one dual natural inhibitor (EGCG) which target EGFR/HER2. In addition, we proposed some EGCG derivatives which were filtered through in silico screening. Structural analysis demonstrated that the coupling of synthetic, natural or newly designed compounds impacts the conformational space of EGFR and HER2 differently. Energetic analysis points out that lapatinib and TAK-285 have better affinity for inactive EGFR than the active EGFR state or HER2, whereas some EGCG derivatives seem to form binding affinities similar to those observed for lapatinib or TAK-285.
表皮生长因子受体（EGFR）的激活始于细胞外结构域的配体结合，导致同源和异源二聚化，进而导致磷酸化，下游信号通路的激活，上调基因表达、增殖和血管生成。EGFR 的表达异常在不同类型癌症的发展中起着关键作用。HER2 是 EGFR 的首选异源二聚化伙伴；这种生物学特性以及高比例的结构同源性已被用于设计针对 EGFR/HER2 的双重合成抑制剂。在此，我们结合结构数据和分子动力学（MD）模拟，并结合 MMGBSA 方法，深入了解两种双重合成物（拉帕替尼和 TAK-285）和一种双重天然抑制剂（EGCG）与 EGFR/HER2 的结合机制。此外，我们还提出了一些经过计算机筛选的 EGCG 衍生物。结构分析表明，合成、天然或新设计化合物的结合会以不同的方式影响 EGFR 和 HER2 的构象空间。能量分析指出，拉帕替尼和 TAK-285 对无活性 EGFR 的亲和力优于活性 EGFR 状态或 HER2，而一些 EGCG 衍生物似乎形成与拉帕替尼或 TAK-285 观察到的类似的结合亲和力。
