基于分子动力学模拟和自由能计算的EGFR-TKIs对EGFR 20外显子插入突变的敏感性研究  

Predicting the sensitivity of different EGFR-TKIs to EGFR exon 20 insertion mutations based on molecular dynamics simulations and free energy calculations

作　　者：陈青青 王剑 吴晓婷 王淅凤 孙一波 卢智奇 CHEN Qingqing;WANG Jian;WU Xiaoting;WANG XiFeng;SUN Yibo;LU Zhiqi(The First People’s Hospital of Linping District,Hangzhou 311100,China)

机构地区：[1]杭州市临平区第一人民医院,浙江杭州311100

出　　处：《浙江实用医学》2024年第4期277-285,共9页Zhejiang Practical Medicine

基　　金：浙江省医药卫生科技计划创新引导专项(2023XY010)。

摘　　要：目的采用分子动力学模拟和自由能计算等技术预测不同表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)对EGFR 20外显子插入突变(EGFR 20 exon insertion mutation,EGFR ex20ins)的敏感性。方法登录PubChem网站,下载奥希替尼(Osimertinib)、伏美替尼(Furmonertinib)、舒沃替尼(Sunvozertinib)的三维分子结构。登录RCSB PDB数据库,下载EGFR ex20ins的蛋白质晶体结构。使用Schr?dinger软件,分别将奥希替尼、伏美替尼、舒沃替尼与EGFR ex20ins晶体结构进行分子对接,并对其结合模式进行分析。随后使用GROMACS软件对3个EGFR-TKIs与EGFR ex20ins复合物进行分子动力学模拟(Molecular Dynamics Simulation,MD)、结合自由能计算、自由能形貌图构建(Free Energy Landscape,FEL)等,分析3个复合物结合的紧密性与稳定性。结果三个小分子均能与EGFR活性位点结合,但是与奥希替尼相比,舒沃替尼、伏美替尼有更低的结合自由能以及更多的氢键数量,更低的溶剂可及表面积(Solvent Accessible Surface Area,SASA)、各氨基酸运动轨迹的均方根方差(Root Mean Square Deviation,RMSD)、均方根波动(Root Mean Square Fluctuation,RMSF)等计算结果也提示伏美替尼、舒沃替尼与EGFR ex20ins结合也较奥希替尼更加紧密与稳定。综上舒沃替尼与EGFR ex20ins的结合紧密性与稳定性最佳,伏美替尼其次,奥希替尼欠佳。结论通过分子动力学模拟、自由能计算等方法可以预测EGFR-TKIs的药物敏感性,这一方法有助于临床选择疗效更优的靶向药物。Objective Using techniques such as molecular dynamics simulations and free energy calculations to predict the sensitivity of different EGFR-TKIs to EGFR 20 exon insertion mutations.Method The three-dimensional molecular structures of Osimertinib,Furmonertinib,and Sunvozertinib were downloaded from the PubChem website.The protein crystal structure of EGFR ex20ins was downloaded from the RCSB PDB database.Schr?觟dinger software was used to dock Osimertinib,Furmonertinib,and Sunvozertinib with the EGFR ex20ins crystal structure,and the binding modes were analyzed.Subsequently,GROMACS software was used to perform molecular dynamics simulations,free energy calculations,and construct free energy landscape maps for the complexes of the three EGFR-TKIs with EGFR ex20ins to analyze the tightness and stability of the three complexes.Result All three small molecules were able to bind to the active site of EGFR,but compared to Osimertinib,Sunvozertinib and Furmonertinib showed lower binding free energies and more hydrogen bonds.Lower RMSD,RMSF,and SASA calculation results also suggested that Furmonertinib and Sunvozertinib binding to EGFR ex20ins was tighter and more stable compared to Osimertinib.Overall,Sunvozertinib showed the best binding tightness and stability with EGFR ex20ins,followed by Furmonertinib,while Osimertinib exhibited the least.Conclusion Molecular dynamics simulations and free energy calculations can be used to predict the drug sensitivity of EGFR-TKIs,aiding in the selection of targeted drugs with better clinical efficacy.

关 键 词：非小细胞肺癌 表皮生长因子受体 分子动力学模拟 

分 类 号：R734.2[医药卫生—肿瘤]