Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt.
Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
J Biomol Struct Dyn. 2023 Aug-Sep;41(13):6134-6144. doi: 10.1080/07391102.2022.2103028. Epub 2022 Jul 29.
Activating mutations in the EGFR kinase domain are known to be a common cause of Non-Small Cell Lung Cancer (NSCLC) and are thus targeted for treatment. First generation Tyrosine Kinase Inhibitors (TKIs) were used to treat NSCLC patients with the known activating mutations L858R and exon 19 deletion but were resisted by a second mutation T790M in the active site of the kinase domain. Second generation members of TKIs have an electrophilic moiety that can form a covalent bond with Cys797 and are effective against T790M EGFR but are toxic because they inhibit WT EGFR as well. Third generation TKIs, like Osimertinib, can bind to and irreversibly inhibit T790M mutants selectively, while sparing the wild-type enzyme. Thus, they possess a better safety profile and a wider therapeutic window. However, the reason behind their selectivity is still not well understood. In this study, computational MD simulations were carried out on Osimertinib in complex with both WT and L858R/T790M Double Mutant (DM) EGFR to provide an insight into the selectivity of Osimertinib and its molecular interactions within the active site. A high-resolution trajectory analysis showed that the key selectivity residues are Val726, met793, and Cys797. Interaction of Osimertinib with these residues is improved due to the T790M mutation which optimizes the ligand orientation for binding, as evident from the RMSD and the distances monitored. These results can provide guidance for the development of more selective 3rd generation EGFR TKIs.Communicated by Ramaswamy H. Sarma.
已知 EGFR 激酶结构域的激活突变是导致非小细胞肺癌（NSCLC）的常见原因，因此成为治疗的靶点。第一代酪氨酸激酶抑制剂（TKI）被用于治疗已知激活突变 L858R 和外显子 19 缺失的 NSCLC 患者，但由于激酶结构域活性位点的第二个突变 T790M，它们会产生耐药性。第二代 TKI 具有亲电部分，可与 Cys797 形成共价键，对 T790M EGFR 有效，但由于它们也抑制 WT EGFR，因此具有毒性。第三代 TKI，如奥希替尼，可以与 T790M 突变体结合并不可逆地选择性抑制，同时保留野生型酶。因此，它们具有更好的安全性和更宽的治疗窗口。然而，它们选择性的背后原因仍未得到很好的理解。在这项研究中，对奥希替尼与 WT 和 L858R/T790M 双突变（DM）EGFR 复合物进行了计算 MD 模拟，以深入了解奥希替尼的选择性及其在活性位点内的分子相互作用。高分辨率轨迹分析表明，关键的选择性残基是 Val726、met793 和 Cys797。由于 T790M 突变优化了配体结合的取向，奥希替尼与这些残基的相互作用得到了改善，这可以从 RMSD 和监测的距离中得到证明。这些结果可以为开发更具选择性的第三代 EGFR TKI 提供指导。由 Ramaswamy H. Sarma 交流。
