Mutations in the kinase domain of the epidermal growth factor receptor (EGFR), a critical biological macromolecule involved in cell growth and division, can lead to drug resistance in patients undergoing chemotherapy with kinase inhibitors. Notably, the emergence of the C797S mutation poses new challenges for targeted EGFR therapy, highlighting the urgent need for agents effective against this triple mutation (L858R/T790M/C797S, EGFR™). Building on our previous finding that sulfonyl and piperidinyl groups significantly contribute to the EGFR™-inhibitor interactions, we have identified the best-in-class inhibitors containing these groups through functional-group-based screening and formally exact absolute binding free-energy calculations. Our new strategy offers greater flexibility than traditional workflows leaning on relative binding free-energy calculations and accommodates ligands with substantial structural variations. The result shows that the top candidate exhibits a binding affinity of -15.8 kcal/mol towards the EGFR™ mutant, surpassing BLU-945, a state-of-the-art fourth-generation inhibitor with a binding free energy of -12.6 kcal/mol. Subsequent free-energy decomposition indicates that the presented top candidate primarily enhances interactions with the K745, D800 and R841 residues, suggesting its potential to overcome resistance from the C797S mutation. Notably, K745 forms highly favorable hydrogen bonds and cation-π interactions with C6. Targeting lysine has emerged as a promising strategy, especially in cases where the C797S mutation renders traditional covalent inhibitors ineffective. We propose that these novel inhibitors represent promising drug candidates for non-small cell lung cancer treatment and offer new strategies to overcome drug resistance caused by EGFR mutation.