Identification of novel inhibitors targeting EGFR L858R/T790M/C797S against NSCLC by molecular docking, MD simulation, and DFT approaches

The resistance of growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC), especially against the EGFR L858R/T790M/C797S mutations, remains an ongoing challenge. In this study, we screened a total of 2.05 million compounds from the ChEMBL database through virtual screening, identifying five promising candidates with high binding affinities and favourable ADMET properties. These candidates were further evaluated through molecular dynamics (MD) simulations, revealing more restricted conformational changes and enhanced stability compared to Osimertinib. Protein-ligand interaction analyses highlighted a broader range of stabilizing interactions in the binding domain. Additionally, the binding free energies of the compounds showed that compounds 1-5 ranged from -34.95 to -45.54 kcal/mol, which were lower compared to Osimertinib (-34.49 kcal/mol), suggesting a stronger binding affinity. Subsequently, density functional theory (DFT) calculations provided further insights into the electronic properties of the compounds, which were essential for understanding the compounds' reactivity and potential interactions with the target protein. In conclusion, the five identified compounds exhibit promising drug-like properties and may serve as lead candidates for the development of new treatments targeting EGFR L858R/T790M/C797S resistance mutations in NSCLC.