虚拟筛选和鉴定EGFRL858R/T790M非共价抑制剂

Discovery of EGFRL858R/T790M Non-covalent Inhibitors via Virtual Screening

目的:基于计算机虚拟筛选和生物活性评价鉴定新的治疗非小细胞肺癌的EGFR酪氨酸激酶EGFRL858R/T790M非共价抑制剂。方法:基于受体-配体复合物结构(PDB ID:5HCZ)构建药效团模型,选择ROC值为0.849的药效团模型对Specs化合物数据库进行筛选,再经过Libdock对接程序进一步过滤,最终选出20个化合物进行EGFRL858R/T790M酶活测试。结果:当化合物浓度为1μmol·L-1时,有7个化合物能够使EGFRL858R/T790M酶活降至52%以下,且对酶的抑制活性高于对照物吉非替尼[(52.77±0.39)%];当浓度为0.1μmol·L^(-1)时,化合物AN-465/42889633[(65.99±2.94)%]、AG-690/40753617[(68.29±6.18)%]和AN-465/43336751[(78.61±7.23)%]对EGFRL858R/T790M的抑制作用仍优于对照物吉非替尼[(80.42±0.62)%];分子对接结果表明3个分子通过氢键、疏水作用力及静电作用力与EGFRL858R/T790M活性部位相结合。结论:AN-465/42889633、AG-690/40753617和AN-465/43336751可作为非共价EGFRL858R/T790M抑制剂的先导化合物进行研究,同时为新型EG-FR抑制剂的研发奠定基础。

Objective:This article aims to discover the EGFRL858R/T790M non-covalent inhibitors based on computer simulation screening and bioactivity evaluation.Methods:A pharmacophore model was constructed based on the structure of the receptor-ligand complex(PDB ID:5HCZ),and a pharmacophore model with a ROC value of 0.849 was selected to screen the Specs compound li-brary,which was later further screened by Libdock docking procedure,and 20 compounds were finally selected for EGFRL858R/T790M enzyme activity test.Results:Seven compounds reduced EGFRL858R/T790M enzyme activity to less than 52%at a concentration of 1μmol·L-1,and the inhibitory activity against the enzyme was higher than that of the control gefitinib[(52.77±0.39)%].It is in-teresting that compounds AN-465/42889633[(65.99±2.94)%],AG-690/40753617[(68.29±6.18)%]and AN-465/43336751[(78.61±7.23)%]at a concentration of 0.1μmol·L^(-1) still showed a better inhibitory effect than the control gefitinib[(80.42±0.62)%]against EGFRL858R/T790M.The docking results show that the three molecules bind to the EGFRL858R/T790M active site by hydrogen bonding,hydrophobic and electrostatic forces.Conclusion:AN-465/42889633,AG-690/40753617 and AN-465/43336751 can be further investigated as lead compounds for the study of non-covalent EGFRL858R/T790M inhibitors,and lay the foundation for the development of novel EGFR inhibitors.