Predicting the sensitivity of different EGFR-TKIs to EGFR exon 20 insertion mutations based on molecular dynamics simulations and free energy calculations
Objective Using techniques such as molecular dynamics simulations and free energy calculations to pre-dict the sensitivity of different EGFR-TKIs to EGFR 20 exon insertion mutations.Method The three-dimensional molecu-lar 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.Schrödinger software was used to dock Osimertinib,Furmonertinib,and Sunvozertinib with the EGFR ex20ins crystal structure,and the binding modes were ana-lyzed.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 dy-namics simulations and free energy calculations can be used to predict the drug sensitivity of EGFR-TKIs,aiding in the se-lection of targeted drugs with better clinical efficacy.
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