ArticleJournal of chemical information and modeling2026
Osimertinib's Proton-Catalyzed, Pseudoconcerted EGFR Inhibition Guides Next-Generation Inhibitor Design.
Article in Journal of chemical information and modeling, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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5 authors.
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Abstract
Third-generation inhibitors such as osimertinib irreversibly inhibit the epidermal growth factor receptor tyrosine kinase (EGFR-TK) via Michael addition to Cys797, yet the mechanism of covalent bond formation remains unsettled. Here, density functional theory-level quantum mechanics/molecular mechanics (QM/MM) computations delineate a proton-catalyzed, pseudoconcerted mechanism for covalent inhibition of EGFR by osimertinib. The computed Gibbs energy profile features a single transition state (TS1) in which Cys797 deprotonation, nucleophilic attack at osimertinib's Michael acceptor, and protonation of the acceptor's carbonyl oxygen by osimertinib's terminal aliphatic aminium occur simultaneously, in contrast to previous stepwise proposals. Natural bond orbital (NBO) analysis shows that carbonyl O-protonation attenuates carbonyl π bonding, increases β-carbon (C
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