WZ系列T790MEGFR抑制剂强效抗肿瘤功效的内在机制探讨  

To Reveal the Essential Factors Which Are Determinant for the Potent Anti-tumor Activity of WZ-series Irreversible Inhibitors against T790M EGFR by Employing DFT Investigation

作　　者：雷凯[1] 刘祥均[1] 陈俐娟[1] 杨明理[1] 向明礼[1] 

机构地区：[1]四川大学华西医院生物治疗国家重点实验室,成都610041

出　　处：《成都工业学院学报》2013年第2期1-5,共5页Journal of Chengdu Technological University

基　　金：国家自然科学基金资助项目"原子和分子团簇的局域-离域极化理论模型及其应用"(批准号:20873088)

摘　　要：为深究WZ系列抑制剂强效抑制突变型表皮生长因子受体(T790M EGFR)的内在机制,用密度泛函理论(DFT)在B3LYP/6-31G(d)计算水平上对进入临床试验阶段的T790M EGFR不可逆抑制剂HKI-272及WZ系列抑制剂进行了研究。结果表明,WZ系列抑制剂在参与Michael加成反应的能力、与T790M EGFR形成的氢键的强度等方面,都优于HKI-272。抑制剂中的参与形成氢键的氢键供体N原子所带的NBO电荷与抑制剂的抗肿瘤功效高度相关。WZ-series irreversible inhibitors are much more potent against T790M EGFR than HKI-272, one of the inhibitors currently under clinical development. All of them were investigated at the B3LYP/6-31G（d） level by employing G03 so as to reveal the essential factors vital for the potent antitumor activities of the WZ-series inhibitors. It was demonstrated that the WZ-series inhibitors are superior to HKI-272 in the capability to participate in Michael addition reaction. It could be speculated from the calculated results that the strength of H-bond formed between WZ-series inhibitors and T790M EGFR would be stronger than that between HKI-272 and the mutant EGFR. It is worth to note that the values of NBO charge of the H-bond donor in the inhibitors are highly relevant to the antitumor activities of the inhibitors.

关 键 词：表皮生长因子受体 不可逆抑制剂 T790M突变 密度泛函理论 

分 类 号：O621.1[理学—有机化学]