2023
DOI: 10.1021/acs.jcim.2c01586
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Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents

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 EGFR L858R/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 innovati… Show more

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Cited by 6 publications
(4 citation statements)
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“…Furthermore, no significant differences were observed in the unbinding path followed by the compounds applying the two sets of 5 CVs. That said, we cannot rule out that other CVs, including those based on the "path" methodology (i.e., S and Z descriptors), 53,54 could provide a more accurate estimation of the absolute RT value. 16,55 Considering the low uncertainty (SEM) associated with the computed log τ values and the satisfactory ability of the 5 CV protocol to discriminate M3 antagonists with long, medium, and short RT, we sought to treat log τ as an empirical descriptor and thus to search for a correlative model between it and experimental RT values, after extending the application of the protocol to the other compounds of the Tautermann data set.…”
Section: ■ Resultsmentioning
confidence: 98%
See 1 more Smart Citation
“…Furthermore, no significant differences were observed in the unbinding path followed by the compounds applying the two sets of 5 CVs. That said, we cannot rule out that other CVs, including those based on the "path" methodology (i.e., S and Z descriptors), 53,54 could provide a more accurate estimation of the absolute RT value. 16,55 Considering the low uncertainty (SEM) associated with the computed log τ values and the satisfactory ability of the 5 CV protocol to discriminate M3 antagonists with long, medium, and short RT, we sought to treat log τ as an empirical descriptor and thus to search for a correlative model between it and experimental RT values, after extending the application of the protocol to the other compounds of the Tautermann data set.…”
Section: ■ Resultsmentioning
confidence: 98%
“…Furthermore, no significant differences were observed in the unbinding path followed by the compounds applying the two sets of 5 CVs. That said, we cannot rule out that other CVs, including those based on the “path” methodology (i.e., S and Z descriptors), 53 , 54 could provide a more accurate estimation of the absolute RT value. 16 , 55 …”
Section: Resultsmentioning
confidence: 98%
“…Furthermore, Arafet et al utilized QM/MM and path collective variables (PCVs) to identify chemical determinants for designing new CKIs targeting the EGFR C797S mutation, aiming to overcome resistance. 14 These rational approaches, increasingly dependent on computational simulations, are shaping the future of covalent drug discovery. 10,12,18 Discovery of CKIs typically involves structure-based design, which integrates an electrophilic warhead (such as acrylamide) into a reversible lead or inhibitor.…”
Section: ■ Introductionmentioning
confidence: 99%
“…The use of computational simulations to investigate medicinal chemistry problem has significantly increased and has been instrumental in advancing the development of covalent inhibitors. For example, quantum mechanics (QM)-based methods have been employed to analyze the covalent binding mechanism of ibrutinib, a drug approved for the treatment of B-cell cancers, to Bruton’s tyrosine kinase (BTK). , Additionally, Callegari et al applied QM/MM MD to investigate the covalent binding process of osimertinib to EGFR, providing insights into resistance mechanisms associated with the L718Q mutation. Furthermore, Arafet et al utilized QM/MM and path collective variables (PCVs) to identify chemical determinants for designing new CKIs targeting the EGFR C797S mutation, aiming to overcome resistance . These rational approaches, increasingly dependent on computational simulations, are shaping the future of covalent drug discovery. ,, …”
Section: Introductionmentioning
confidence: 99%