Discovery of EGFRL858R/T790M Non-covalent Inhibitors via Virtual Screening
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 1 μmol·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 0.1 μmol·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.
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