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 (Delta A = -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.

Quantum mechanics/molecular mechanics modeling of covalent addition between EGFR-cysteine 797 and N -(4-Anilinoquinazolin-6-yl) acrylamide / Capoferri, Luigi; Lodola, Alessio; Rivara, Silvia; Mor, Marco. - In: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - ISSN 1549-9596. - 55:3(2015), pp. 589-599. [10.1021/ci500720e]

Quantum mechanics/molecular mechanics modeling of covalent addition between EGFR-cysteine 797 and N -(4-Anilinoquinazolin-6-yl) acrylamide

CAPOFERRI, LUIGI;LODOLA, Alessio;RIVARA, Silvia;MOR, Marco
2015-01-01

Abstract

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 (Delta A = -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.
2015
Quantum mechanics/molecular mechanics modeling of covalent addition between EGFR-cysteine 797 and N -(4-Anilinoquinazolin-6-yl) acrylamide / Capoferri, Luigi; Lodola, Alessio; Rivara, Silvia; Mor, Marco. - In: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - ISSN 1549-9596. - 55:3(2015), pp. 589-599. [10.1021/ci500720e]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2797368
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