Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents
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comunitat-uji-handle2:10234/160292
comunitat-uji-handle3:10234/160293
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Title
Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible AgentsAuthor (s)
Date
2023-02-10Publisher
American Chemical SocietyISSN
1549-9596; 1549-960XBibliographic citation
Arafet, K., Scalvini, L., Galvani, F., Martí, S., Moliner, V., Mor, M., & Lodola, A. (2023). Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents. Journal of Chemical Information and Modeling, 63(4), 1301-1312.Type
info:eu-repo/semantics/articleVersion
info:eu-repo/semantics/publishedVersionSubject
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 ... [+]
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. [-]
Is part of
J. Chem. Inf. Model. 2023, 63, 1301−1312Funder Name
Generalitat Valenciana | Ministerio de Ciencia, Innovación y Universidades | University of Parma
Project code
APOSTD/2020/015 | PGC2021-23332OB-C21 | PROMETEO, CIPROM/2021/079 | POR FSE 2014/2020
Rights
© 2023 The Authors. Published by American Chemical Society
info:eu-repo/semantics/openAccess
info:eu-repo/semantics/openAccess
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