Probing the Effect of Protein and Inhibitor Conformational Flexibility on the Reaction of Rocelitinib-Like Covalent Inhibitors of Epidermal Growth Factor Receptor. A Quantum Mechanics/Molecular Mechanics Study

Abstract

, can undergo reaction with rate-determining barriers of ∼20 kcal/mol. Interestingly, the nature of the rate-determining step for Rocelitinib-like inhibitors was found to be either direct nucleophilic attack or keto-enol tautomerization, depending on the precise protein and inhibitor conformation.