Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents
Visualitza/
Impacte
Scholar |
Altres documents de l'autoria: Arafet Cruz, Kemel; Scalvini, Laura; Galvani, Francesca; Martí, Sergio; Moliner, Vicent; Mor, Marco; Lodola, Alessio
Metadades
Mostra el registre complet de l'elementcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/160292
comunitat-uji-handle3:10234/160293
comunitat-uji-handle4:
INVESTIGACIONMetadades
Títol
Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible AgentsAutoria
Data de publicació
2023-02-10Editor
American Chemical SocietyISSN
1549-9596; 1549-960XCita bibliogràfica
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.Tipus de document
info:eu-repo/semantics/articleVersió
info:eu-repo/semantics/publishedVersionParaules clau / Matèries
Resum
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. [-]
Publicat a
J. Chem. Inf. Model. 2023, 63, 1301−1312Entitat finançadora
Generalitat Valenciana | Ministerio de Ciencia, Innovación y Universidades | University of Parma
Codi del projecte o subvenció
APOSTD/2020/015 | PGC2021-23332OB-C21 | PROMETEO, CIPROM/2021/079 | POR FSE 2014/2020
Drets d'accés
© 2023 The Authors. Published by American Chemical Society
info:eu-repo/semantics/openAccess
info:eu-repo/semantics/openAccess
Apareix a les col.leccions
- INAM_Articles [528]