QM/MM Simulations of Afatinib-EGFR Addition: The Role of ß-Dimethylaminomethyl Substitution.
J Chem Theory Comput
; 20(13): 5528-5538, 2024 Jul 09.
Article
in En
| MEDLINE
| ID: mdl-38877999
ABSTRACT
Acrylamides are the most commonly used warheads of targeted covalent inhibitors (TCIs) directed at cysteines; however, the reaction mechanisms of acrylamides in proteins remain controversial, particularly for those involving protonated or unreactive cysteines. Using the combined semiempirical quantum mechanics (QM)/molecular mechanics (MM) free energy simulations, we investigated the reaction between afatinib, the first TCI drug for cancer treatment, and Cys797 in the EGFR kinase. Afatinib contains a ß-dimethylaminomethyl (ß-DMAM) substitution which has been shown to enhance the intrinsic reactivity and potency against EGFR for related inhibitors. Two hypothesized reaction mechanisms were tested. Our data suggest that Cys797 becomes deprotonated in the presence of afatinib, and the reaction proceeds via a classical Michael addition mechanism, with Asp800 stabilizing the ion-pair reactant state ß-DMAM+/C797- and the transition state of the nucleophilic attack. Our work elucidates an important structure-activity relationship of acrylamides in proteins.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quantum Theory
/
Molecular Dynamics Simulation
/
ErbB Receptors
/
Afatinib
Limits:
Humans
Language:
En
Journal:
J Chem Theory Comput
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Estados Unidos