Accelerating Scaffold Hopping in Fourth-Generation Epidermal Growth Factor Receptor Inhibitors via Multilevel Virtual Screening

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-09-30 DOI:10.1021/acsmedchemlett.5c00194

Zhiqi Sun, , , Donghui Huo, , , Jiangyu Guo, , and , Aixia Yan*,

{"title":"Accelerating Scaffold Hopping in Fourth-Generation Epidermal Growth Factor Receptor Inhibitors via Multilevel Virtual Screening","authors":"Zhiqi Sun, , , Donghui Huo, , , Jiangyu Guo, , and , Aixia Yan*, ","doi":"10.1021/acsmedchemlett.5c00194","DOIUrl":null,"url":null,"abstract":"The epidermal growth factor receptor (EGFR) family plays a crucial role in regulating cell proliferation, apoptosis, and differentiation. However, challenges related to drug resistance have emerged in the clinical applications of this family. This study addresses resistance mediated by the L858R/T790M/C797S EGFR mutation through a multilevel virtual screening strategy that integrates 3D shape similarity screening, multitask deep learning-based activity prediction, molecular docking, and molecular dynamics simulations. From 18 million drug-like molecules screened, 12 candidates underwent in vitro enzymatic testing, leading to the identification of three novel scaffold inhibitors. Compound L15 demonstrated potent inhibitory activity against the L858R/T790M/C797S mutant EGFR (IC50 = 16.43 nM), exhibiting 5-fold selectivity over wild-type EGFR (IC50 = 80.96 nM). Additionally, it exhibited comparable efficacy against the d746-750/T790M/C797S variant (IC50 = 16.53 nM). Interaction analysis revealed that L15 stabilizes its binding conformation via dominant hydrophobic interactions with LEU718 and LEU792, as revealed by free energy decomposition. This work establishes a systematic multilevel virtual screening strategy to overcome EGFR resistance, providing structural and mechanistic insights for the rational design of fourth-generation inhibitors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 10","pages":"1927–1934"},"PeriodicalIF":4.0000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00194","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

The epidermal growth factor receptor (EGFR) family plays a crucial role in regulating cell proliferation, apoptosis, and differentiation. However, challenges related to drug resistance have emerged in the clinical applications of this family. This study addresses resistance mediated by the L858R/T790M/C797S EGFR mutation through a multilevel virtual screening strategy that integrates 3D shape similarity screening, multitask deep learning-based activity prediction, molecular docking, and molecular dynamics simulations. From 18 million drug-like molecules screened, 12 candidates underwent in vitro enzymatic testing, leading to the identification of three novel scaffold inhibitors. Compound L15 demonstrated potent inhibitory activity against the L858R/T790M/C797S mutant EGFR (IC₅₀ = 16.43 nM), exhibiting 5-fold selectivity over wild-type EGFR (IC₅₀ = 80.96 nM). Additionally, it exhibited comparable efficacy against the d746-750/T790M/C797S variant (IC₅₀ = 16.53 nM). Interaction analysis revealed that L15 stabilizes its binding conformation via dominant hydrophobic interactions with LEU718 and LEU792, as revealed by free energy decomposition. This work establishes a systematic multilevel virtual screening strategy to overcome EGFR resistance, providing structural and mechanistic insights for the rational design of fourth-generation inhibitors.

Abstract Image

查看原文本刊更多论文

第四代表皮生长因子受体抑制剂通过多层虚拟筛选加速支架跳跃

表皮生长因子受体（EGFR）家族在调节细胞增殖、凋亡和分化中起着至关重要的作用。然而，在该家族的临床应用中出现了与耐药相关的挑战。本研究通过多层虚拟筛选策略解决了L858R/T790M/C797S EGFR突变介导的抗性，该策略集成了3D形状相似性筛选、基于多任务深度学习的活动预测、分子对接和分子动力学模拟。从筛选的1800万个药物样分子中，12个候选分子进行了体外酶促测试，从而鉴定出三种新的支架抑制剂。化合物L15对L858R/T790M/C797S突变型EGFR具有较强的抑制活性（IC50 = 16.43 nM），其选择性是野生型EGFR的5倍（IC50 = 80.96 nM）。此外，它对d746-750/T790M/C797S变异具有相当的疗效（IC50 = 16.53 nM）。相互作用分析表明，L15通过与LEU718和LEU792的主要疏水相互作用来稳定其结合构象，这是由自由能分解揭示的。这项工作建立了一个系统的多层虚拟筛选策略来克服EGFR耐药性，为第四代抑制剂的合理设计提供了结构和机制上的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.