Inhibition of Ponatinib on wild-type and T315I mutant BCR-ABL1 kinase based on molecular simulation

doi:10.16085/j.issn.1000-6613.2017-0891

Abstract

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.

Key words: molecular simulation, enzyme, T315I mutant, Ponatinib, kinetic theory, reactivity

摘要： 药物普纳替尼（Ponatinib）对野生型和T315I突变型BCR-ABL1激酶均有较强抑制作用，然而其抑制机理仍然未知。为了更好地了解Ponatinib与BCR-ABL1激酶的作用机理，本文首先运用分子动力学模拟方法研究Ponatinib对BCR-ABL1激酶构象变化的影响，然后采用MM-PBSA方法计算复合物的结合自由能。结果表明：Ponatinib诱导野生型BCR-ABL1激酶P-loop和铰链区相互靠近，导致野生型激酶结合口袋关闭，有利于激酶与药物结合；而Ponatinib诱导T315I突变型BCR-ABL1激酶P-loop和铰链区相互远离，导致T315I突变型激酶结合口袋打开，对激酶与药物结合不利；Ponatinib与野生型以及T315I突变型BCR-ABL1激酶的结合自由能分别为-58.57 kcal/mol和-43.54kcal/mol，Ponatinib对野生型BCR-ABL1激酶的抑制能力明显强于T315I突变体，与文献报道的实验抑制活性结果一致。研究结果对认识靶点蛋白和抑制剂分子机制以及设计新药有重要意义。

关键词: 分子模拟, 酶, T315I突变, 普纳替尼, 动力学理论, 活性

CLC Number:

Q754

CHEN Qing, WANG Jianyi. Inhibition of Ponatinib on wild-type and T315I mutant BCR-ABL1 kinase based on molecular simulation[J]. Chemical Industry and Engineering Progress, 2018, 37(02): 702-707.

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(02): 702-707.

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