Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi, India.
J Biomol Struct Dyn. 2023 Jul;41(10):4534-4548. doi: 10.1080/07391102.2022.2068650. Epub 2022 May 4.
Tyrosine kinase (TK) is an important protein responsible for phosphorylation of variety of proteins that helps in signal transduction process in transferring signal to regulate various physiological and biochemical processes. Drugs inhibiting signal transduction pathways can be a very rational approach to inhibit cellular physiological and biochemical process. Tyrosine kinase inhibitors are a wide family of drugs that have been used successfully in cancer chemotherapy. Certain mutations around the catalytic cleft may cause conformational changes at binding site and leads to decrease in inhibitor sensitivity to TK mutants. EGFR mutation is the first recognized acquired resistance after tyrosine kinase inhibitor therapy that leads to resistant to first generation TKI in about 50% of non-small cell lung carcinoma patients. Third generation EGFR-TKIs bind irreversibly to the C797, which is present in the ATP-binding pocket. The present work provides a molecular mechanism for understanding the Gefitinib and Osimertinib sensitivities with the EGFR, EGFR, EGFR, EGFR mutants using molecular modelling techniques. Changes in response against Gefitinib and Osimertinib were observed with the change of amino acids at the tyrosine kinase domain of EGFR and its mutants (EGFR, EGFR, EGFR). RMSD, RMSF and binding energies calculation well correlates with the change in clinical observation.Communicated by Ramaswamy H. Sarma.
酪氨酸激酶（TK）是一种重要的蛋白质，负责磷酸化多种蛋白质，有助于信号转导过程中信号的传递，调节各种生理和生化过程。抑制信号转导途径的药物是抑制细胞生理和生化过程的一种非常合理的方法。酪氨酸激酶抑制剂是一类已成功用于癌症化疗的广泛的药物家族。催化裂缝周围的某些突变可能导致结合部位的构象变化，从而降低抑制剂对 TK 突变体的敏感性。表皮生长因子受体（EGFR）突变是酪氨酸激酶抑制剂治疗后首先被识别的获得性耐药，导致大约 50%的非小细胞肺癌患者对第一代 TKI 产生耐药。第三代 EGFR-TKIs 不可逆地与位于 ATP 结合口袋中的 C797 结合。本工作通过分子建模技术，为理解吉非替尼和奥希替尼与 EGFR、EGFR、EGFR 突变体的敏感性提供了分子机制。在 EGFR 及其突变体（EGFR、EGFR、EGFR）的酪氨酸激酶结构域的氨基酸变化观察到对吉非替尼和奥希替尼的反应变化。RMSD、RMSF 和结合能计算与临床观察的变化很好地相关。由 Ramaswamy H. Sarma 交流。
