一类伊马替尼衍生物酪氨酸激酶抑制剂作用模式的理论研究

Theoretical research on interaction modes of imatinib analogues Bcr-Abl inhibitors

第1代Bcr-Abl抑制剂伊马替尼问世以来取得了巨大的商业成功。本文对酪氨酸激酶和伊马替尼、尼罗替尼复合物晶体的结构(PDB ID:2HYY、3CS9)中伊马替尼、尼罗替尼的活性结构、药效团进行了分析研究,探讨了酪氨酸激酶与抑制剂的相互作用模式。研究表明伊马替尼分子结构中哌嗪基部分与酶作用较弱,没有明显的药效团,适合在此部分结构进行结构改造。基于69个伊马替尼衍生物抑制剂的结构和活性数据,利用遗传算法,建立了合理伊马替尼衍生物的定量构效关系。确定的酪氨酸激酶与抑制剂的作用模式,可以指导抑制剂的设计,用于开发新型抗癌药物。

The first-generation Bcr-Abl inhibitor imatinib has achieved great clinical success and became the first-line drug for the treatment of CML, However, emerging acquired resistance to this drug can be a major challenge. Based on the crystal structure of Imatinib and second-generation Bcr-Abl inhibitor nilotinib tyrosine kinase complex （PDB ID： 2HYY, 3CS9）, the active structure and pharmacophores of imatinib and nilotinib, and the interaction between imatinib and nilotinib with the active site of tyrosine kinase have been explored. It was found that the methylpiperazin group of imatinib bound to the active site of tyrosine kinase is weaker than the substructure of nilotinib, and there are no obvious pharmacophores, so this part structure of imatinib can be rebuilt like nilotinib. The structures of 69 imatinib analogues Bcr-Abl inhibitors were calculated by using PM3 semiempirical quantum chemistry methods, and the 2D-QSAR of inhibitors were studied by genetic algorithm method. It was found that reasonable substructures and hydrophobic interaction of terminal groups at piperazin group side are important to strengthen the combination with tyrosine kinase, increases their medical effectiveness, and capable of overcoming clinical acquired resistance against imatinib.