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核心技术专利：CN118964589B侵权必究
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EGFR C797S 中 Lys745 磺化作用的机制建模揭示了抑制剂活性的化学决定因素，并区分了可逆和不可逆试剂。

Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents.

机构信息

Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I- 43124 Parma, Italy.

BioComp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, 12071 Castelló, Spain.

出版信息

J Chem Inf Model. 2023 Feb 27;63(4):1301-1312. doi: 10.1021/acs.jcim.2c01586. Epub 2023 Feb 10.

DOI:10.1021/acs.jcim.2c01586
PMID:36762429
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9976278/
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 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.

摘要

靶向共价抑制剂在药物发现中具有广阔的前景，尤其是对于激酶而言。由于 C797S 突变的出现，靶向表皮生长因子受体 (EGFR) 的催化赖氨酸已成为克服耐药性的新策略。已经报道了能够通过赖氨酸 745 的磺酰化来抑制 EGFR 的磺酰氟衍生物。然而，该过程的原子细节仍知之甚少。在这里，我们描述了一类新型化合物的抑制机制，这些化合物通过硫（VI）氟交换 (SuFEx) 过程，借助混合量子力学/分子力学 (QM/MM) 和路径集体变量 (PCVs) 方法，与 EGFR 的催化赖氨酸发生共价结合。我们的模拟确定了导致靶向赖氨酸 745 的试剂不可逆活性的化学决定因素，并为进一步优化磺酰氟试剂提供了线索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/4d3ad5953ad3/ci2c01586_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/f25bd35479af/ci2c01586_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/1b6a89cd4ba5/ci2c01586_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/5916d0919049/ci2c01586_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/59775c54b2c7/ci2c01586_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/fa1a0b520d85/ci2c01586_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/5aa6ffb69c77/ci2c01586_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/5a759a49e772/ci2c01586_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/befd4462c845/ci2c01586_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/0787e7864223/ci2c01586_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/95e80e768e1a/ci2c01586_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/ca04e996eaa7/ci2c01586_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/bad9375c72cd/ci2c01586_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/4d3ad5953ad3/ci2c01586_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/f25bd35479af/ci2c01586_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/1b6a89cd4ba5/ci2c01586_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/5916d0919049/ci2c01586_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/59775c54b2c7/ci2c01586_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/fa1a0b520d85/ci2c01586_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/5aa6ffb69c77/ci2c01586_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/5a759a49e772/ci2c01586_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/befd4462c845/ci2c01586_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/0787e7864223/ci2c01586_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/95e80e768e1a/ci2c01586_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/ca04e996eaa7/ci2c01586_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/bad9375c72cd/ci2c01586_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfa8/9976278/4d3ad5953ad3/ci2c01586_0012.jpg

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[2]
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本文引用的文献

[1]
Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome.

ACS Chem Biol. 2023-2-17

[2]
QM/MM Simulations Reveal the Determinants of Carbapenemase Activity in Class A β-Lactamases.

ACS Infect Dis. 2022-8-12

[3]
Emerging strategies to overcome resistance to third-generation EGFR inhibitors.

J Hematol Oncol. 2022-7-15

[4]
Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.

J Med Chem. 2022-7-28

[5]
Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency.

J Chem Inf Model. 2022-6-13

[6]
Free-Energy Simulations Support a Lipophilic Binding Route for Melatonin Receptors.

J Chem Inf Model. 2022-1-10

[7]
A sulfonyl fluoride derivative inhibits EGFR by covalent modification of the catalytic lysine.

Eur J Med Chem. 2021-12-5

[8]
Mechanism of inhibition of SARS-CoV-2 M by peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity.

Chem Sci. 2020-11-27

[9]
Fighting tertiary mutations in EGFR-driven lung-cancers: Current advances and future perspectives in medicinal chemistry.

Biochem Pharmacol. 2021-8

[10]
Catalysis by the JmjC histone demethylase KDM4A integrates substrate dynamics, correlated motions and molecular orbital control.

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