Osimertinib's Proton-Catalyzed, Pseudoconcerted EGFR Inhibition Guides Next-Generation Inhibitor Design.

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 car

SUBMITTER: Kondo A 

PROVIDER: S-EPMC12848964 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature