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.　©　2025　Elsevier　Inc.