Quantum Mechanics/Molecular Mechanics Modeling of Covalent Addition between EGFR–Cysteine 797 and N-(4-Anilinoquinazolin-6-yl) Acrylamide
| Autor: | Luigi Capoferri, Silvia Rivara, Marco Mor, Alessio Lodola |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Protein Conformation Stereochemistry General Chemical Engineering Molecular Dynamics Simulation Library and Information Sciences Alkylation Molecular mechanics chemistry.chemical_compound Catalytic Domain Quantum mechanics Reactivity (chemistry) Cysteine Acrylamides Aspartic Acid biology Chemistry Active site General Chemistry Computer Science Applications ErbB Receptors Covalent bond Acrylamide Quinazolines biology.protein Quantum Theory Umbrella sampling |
| Zdroj: | Journal of Chemical Information and Modeling. 55:589-599 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/ci500720e |
| Popis: | Irreversible epidermal growth factor receptor (EGFR) inhibitors can circumvent resistance to first-generation ATP-competitive inhibitors in the treatment of nonsmall-cell lung cancer. They covalently bind a noncatalytic cysteine (Cys797) at the surface of EGFR active site by an acrylamide warhead. Herein, we used a hybrid quantum mechanics/molecular mechanics (QM/MM) potential in combination with umbrella sampling in the path-collective variable space to investigate the mechanism of alkylation of Cys797 by the prototypical covalent inhibitor N-(4-anilinoquinazolin-6-yl) acrylamide. Calculations show that Cys797 reacts with the acrylamide group of the inhibitor through a direct addition mechanism, with Asp800 acting as a general base/general acid in distinct steps of the reaction. The obtained reaction free energy is negative (ΔA = -12 kcal/mol) consistent with the spontaneous and irreversible alkylation of Cys797 by N-(4-anilinoquinazolin-6-yl) acrylamide. Our calculations identify desolvation of Cys797 thiolate anion as a key step of the alkylation process, indicating that changes in the intrinsic reactivity of the acrylamide would have only a minor impact on the inhibitor potency. |
| Databáze: | OpenAIRE |
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