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Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents
dc.contributor.author | Arafet Cruz, Kemel | |
dc.contributor.author | Scalvini, Laura | |
dc.contributor.author | Galvani, Francesca | |
dc.contributor.author | Martí, Sergio | |
dc.contributor.author | Moliner, Vicent | |
dc.contributor.author | Mor, Marco | |
dc.contributor.author | Lodola, Alessio | |
dc.date.accessioned | 2023-05-29T10:30:11Z | |
dc.date.available | 2023-05-29T10:30:11Z | |
dc.date.issued | 2023-02-10 | |
dc.identifier.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. | ca_CA |
dc.identifier.issn | 1549-9596 | |
dc.identifier.issn | 1549-960X | |
dc.identifier.uri | http://hdl.handle.net/10234/202634 | |
dc.description.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. | ca_CA |
dc.format.extent | 12 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | American Chemical Society | ca_CA |
dc.relation.isPartOf | J. Chem. Inf. Model. 2023, 63, 1301−1312 | ca_CA |
dc.relation.uri | The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.2c01586. Detailed description of the model building and equilibration procedure, technical details regarding the QM/MM simulations performed at the PM6/AMBER level and cluster model calculations; computational results and details for alternative mechanisms for sulfonylation by AM, US, and PCVs simulations; charge analysis of QM atoms for mechanisms m1–m3; details of characterization of the TSs at the DFT/AMBER level of theory; and frontier orbital energies for modeled inhibitors (PDF) Geometries of the transition state (TS1) for EGFR sulfonylation by XO44, UPR1444, and UPR1433 (ZIP) Input files of Path-CVs simulations (round 6; ZIP) | ca_CA |
dc.rights | © 2023 The Authors. Published by American Chemical Society | ca_CA |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | ca_CA |
dc.subject | anions | ca_CA |
dc.subject | inhibitors | ca_CA |
dc.subject | mathematical methods | ca_CA |
dc.subject | monomers | ca_CA |
dc.subject | peptides and proteins | ca_CA |
dc.title | Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | https://doi.org/10.1021/acs.jcim.2c01586 | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.type.version | info:eu-repo/semantics/publishedVersion | ca_CA |
project.funder.name | Generalitat Valenciana | ca_CA |
project.funder.name | Ministerio de Ciencia, Innovación y Universidades | ca_CA |
project.funder.name | University of Parma | ca_CA |
oaire.awardNumber | APOSTD/2020/015 | ca_CA |
oaire.awardNumber | PGC2021-23332OB-C21 | ca_CA |
oaire.awardNumber | PROMETEO, CIPROM/2021/079 | ca_CA |
oaire.awardNumber | POR FSE 2014/2020 | ca_CA |
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