桑鹏, 李智, 杨力权, 宋玲. 基于分子动力学模拟和自由能计算的非小细胞肺癌对克唑替尼(crizotinib)耐药性研究[J]. 云南大学学报(自然科学版), 2020, 42(4): 760-767. doi: 10.7540/j.ynu.20200002
引用本文: 桑鹏, 李智, 杨力权, 宋玲. 基于分子动力学模拟和自由能计算的非小细胞肺癌对克唑替尼(crizotinib)耐药性研究[J]. 云南大学学报(自然科学版), 2020, 42(4): 760-767. doi: 10.7540/j.ynu.20200002
SANG Peng, LI Zhi, YANG Li-quan, SONG Ling. Insight into crizotinib resistance of non-small cell lung cancer derived from molecular dynamics simulations and free energy analysis[J]. Journal of Yunnan University: Natural Sciences Edition, 2020, 42(4): 760-767. DOI: 10.7540/j.ynu.20200002
Citation: SANG Peng, LI Zhi, YANG Li-quan, SONG Ling. Insight into crizotinib resistance of non-small cell lung cancer derived from molecular dynamics simulations and free energy analysis[J]. Journal of Yunnan University: Natural Sciences Edition, 2020, 42(4): 760-767. DOI: 10.7540/j.ynu.20200002

基于分子动力学模拟和自由能计算的非小细胞肺癌对克唑替尼(crizotinib)耐药性研究

Insight into crizotinib resistance of non-small cell lung cancer derived from molecular dynamics simulations and free energy analysis

  • 摘要: 为了研究间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)F1174V突变引起非小细胞肺癌患者对crizotinib的耐药性机制,使用分子动力学模拟(molecular dynamics simulations, MD). 本质动力学(essential dynamics, ED)分析及分子力学泊松-玻尔兹曼比表面积(molecular mechanics Poisson-Boltzmann surface area, MM-PBSA)结合自由能计算等方法研究了野生型及F1174V突变型ALK与克唑替尼(crizotinib)结合模式的差异. MD模拟和ED分析结果表明,F1174V突变导致ALK的crizotinib结合口袋部位构象柔性降低,由此可能造成药物进出ALK速度减慢,影响药物发挥正常作用. MM-PBSA结合自由能计算结果表明,F1174V突变造成ALK与crizotinib的结合能力降低. 进一步构建了野生型和突变型ALK的自由能图谱(free energy landscape,FEL),并选取了二者最主要自由能井的代表性结构进行比较. 结果表明,F1174V突变可以显著改变ALK的构象,特别是可以通过收缩P-环和缩小结合口袋来减弱其与crizotinib的相互作用. 研究有助于揭示基于ALK的靶向药物耐药机制,并为开发抗非小细胞肺癌药物提供帮助.

     

    Abstract: In order to investigate the effect of anaplastic lymphoma kinase (ALK) F1174V mutation on the interaction of ALK and crizotinib, we performed molecular dynamics (MD) simulations, essential dynamics (ED) analyses and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on wild-type (WT) and mutant ALK-crizotinib complex. Our MD simulations and ED analysis indicate that the F1174V mutation can decrease the flexibility of ALK, especially for the crizotinib binding pocket, which can result in decreased kinetics of drug entrance and egress. The MM-PBSA calculations demonstrate that the mutant exhibits weakened cofactor binding affinity with crizotinib in comparison with WT. Comparison between representative structures of the constructed free energy landscape (FEL) of WT and mutant suggests that the F1174V mutation significantly changes the ALK structure, thereby weakens the interactions with crizotinib by shrinking the P-loop and narrowing the pocket volume. Our study sheds light on the mechanism of ALK targeted drug resistance, providing insight into the design of potent and effective drug for non-small cell lung cancer.

     

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