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.
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