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Updated: Aug 10, 2025

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and
Kemel Arafet1,2, Laura Scalvini1, Francesca Galvani1
1Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I- 43124 Parma, Italy.
Abstract:
Targeted covalent inhibitors hold promise for drug discovery, particularly for kinases. Targeting the catalytic lysine of epidermal growth factor receptor (EGFR) has attracted attention as a new strategy to overcome resistance due to the emergence of C797S mutation. Sulfonyl fluoride derivatives able to inhibit EGFRL858R/T790M/C797S by sulfonylation of Lys745 have been reported. However, atomistic details of this process are still poorly understood. Here, we describe the mechanism of inhibition of an innovative class of compounds that covalently engage the catalytic lysine of EGFR, through a sulfur(VI) fluoride exchange (SuFEx) process, with the help of hybrid quantum mechanics/molecular mechanics (QM/MM) and path collective variables (PCVs) approaches. Our simulations identify the chemical determinants accounting for the irreversible activity of agents targeting Lys745 and provide hints for the further optimization of sulfonyl fluoride agents.
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