化工进展2018，Vol.37Issue(2)：702-707,6.DOI:10.16085/j.issn.1000-6613.2017-0891
Ponatinib抑制野生型和T315I突变型BCR-ABL1激酶的分子模拟
Inhibition of Ponatinib on wild-type and T315I mutant BCR-ABL1 kinase based on molecular simulation
摘要
Abstract
The drug Ponatinib had a strong inhibitory effect on wild-type and T315I mutant BCR-ABL1 kinase,but its inhibition mechanism was still unknown.To have a better understanding of the interaction mechanism between Ponatinib and BCR-ABL1 kinase,the effect of Ponatinib on the conformational changes of BCR-ABL1 kinase was studied by molecular dynamics simulation at first,and then the binding free energy of complex was calculated by the MM-PBSA method.The results indicated that the P-loop and hinge region of wild-type BCR-ABL1 kinase approached each other induced by Ponatinib,leading to the closure of the binding pocket of wild-type BCR-ABL1 kinase,which would be favorable to the binding of drug.In contrast,the P-loop and hinge region of T315I mutant BCR-ABL1 kinase move far away from each other induced by Ponatinib,resulting in the opening of the binding pocket of T315I mutant BCR-ABL1 kinase,which was no advantage for kinase binding with drug.The binding free energy of Ponatinib bound to wild-type and T315I mutant BCR-ABL1 kinase were -58.57kcal/mol and -43.54kcal/mol,respectively.The results showed that the inhibitory ability of Ponatinib on wild-type BCR-ABL1 kinase was significantly stronger than that of T315I mutant,which was consistent with the experimental inhibition activity reported in the literature.This study provided important understanding of the molecular mechanism of target proteins and inhibitors and the design of a new drug.关键词
分子模拟/酶/T315I突变/普纳替尼/动力学理论/活性Key words
molecular simulation/enzyme/T315I mutant/Ponatinib/kinetic theory/reactivity分类
生物科学引用本文复制引用
陈清,王坚毅..Ponatinib抑制野生型和T315I突变型BCR-ABL1激酶的分子模拟[J].化工进展,2018,37(2):702-707,6.基金项目
国家自然科学基金项目(21262004). （21262004）
