ArticleJournal of chemical theory and computation2024
QM/MM Simulations of Afatinib-EGFR Addition: The Role of β-Dimethylaminomethyl Substitution.
Article in Journal of chemical theory and computation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Targeting FLT3 in Acute Myeloid Leukemia: Structural Insights and Key Challenges.ACS bio & med chem Au · 2026Review
- Generating Molecular Diversity via Addition of Nucleophiles to Electron-Deficient [3]Dendralenes: An Exploratory Study.The Journal of organic chemistry · 2026Article
- Osimertinib's Proton-Catalyzed, Pseudoconcerted EGFR Inhibition Guides Next-Generation Inhibitor Design.Journal of chemical information and modeling · 2026Article
- A Silver-Copper-Aluminum Layered Double Hydroxide Sensor for Sensitive Determination of Anticancer Agent Afatinib in Bulk and Biological Fluids.ACS omega · 2025Article
- Challenges and Advances in the Simulation of Targeted Covalent Inhibitors Using Quantum Computing.The journal of physical chemistry letters · 2025Review
- Activity-based protein profiling guided new target identification of quinazoline derivatives for expediting bactericide discovery: Activity-based protein profiling derived new target discovery of antibacterial quinazolines.Journal of advanced research · 2025Article
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4 authors.
Funding
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 β-dimethylaminomethyl (β-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 β-DMAM
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Registered trials
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