Abstract

Background/Objectives: The EGFR T790M mutation drives lung cancer resistance by sterically hindering inhibitors and restoring ATP affinity. As C797S mutations render covalent inhibitors obsolete, novel non-covalent strategies are critical. This study identifies inhibitors that redefine the mutant methionine sulfur as a primary stabilizing anchor rather than a liability. Methods: A generative AI framework (DrugEx) sampled 100,000 molecules, prioritized via QSAR classification (ROC-AUC: 0.91 ± 0.01) and Applicability Domain (AD) mapping. The workflow was de-risked through retrospective benchmarking against the DUD-E database (35,590 molecules), achieving a 1% Enrichment Factor of 5.19. Lead candidates underwent 100 ns all-atom molecular dynamics (MD) simulations. Mechanistic stability was quantified via Free Energy Landscape (FEL) analysis and ensemble-averaged MM-GBSA binding free energy calculations. Results: Candidate 106 demonstrated exceptional mutation tolerance by redistributing interactions toward the Met790 sulfur atom. MD analysis confirmed potency is dictated by successful recruitment of the thioether environment, locking the complex within a narrow thermodynamic basin. Candidate 106 maintained stable binding (−11.0 kcal/mol) corroborated by an equipotent MM-GBSA ΔGbind of −50.51 kcal/mol in the mutant system, driven by persistent π-sulfur contacts (85% occupancy). Conclusions: These results indicates that potential T790M resistance bypass is achievable by exploiting the gatekeeper methionine’s electronic environment. This modeled mutation-aware framework provides a candidate non-covalent strategy to be validated in future wet-lab campaigns.

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