Identification and interaction mechanism of novel small molecule antagonists targeting CC chemokine receptor 1/3/5 for treatment of non-small cell lung cancer.

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Xiaomeng Wang, Juan Wang, Qiao Fu, Jing Luo, Mao Shu, Zhihua Lin
{"title":"Identification and interaction mechanism of novel small molecule antagonists targeting CC chemokine receptor 1/3/5 for treatment of non-small cell lung cancer.","authors":"Xiaomeng Wang, Juan Wang, Qiao Fu, Jing Luo, Mao Shu, Zhihua Lin","doi":"10.1007/s11030-024-11025-1","DOIUrl":null,"url":null,"abstract":"<p><p>Non-Small Cell Lung Cancer (NSCLC) was one of the most prevalent forms of lung cancer. Due to its ease of invasion and migration, the five-year survival rate was relatively low. Therefore, new strategies for NSCLC treatment were needed. CC chemokine receptor 1/3/5 (CCR1/CCR3/CCR5), a member of the G-protein coupled receptor family, could promote the migration and invasion of NSCLC cells by binding to related chemokines. Consequently, targeting CCR1, CCR3 and CCR5 might prevent the progression of the disease. So far, no compound had been reported as a common antagonist for CCR1, CCR3, and CCR5. In this research, we utilized virtual screening and structural optimization to obtain compound 5, which effectively inhibited the migration and invasion of NSCLC cells. Meanwhile, Western Blot and Enzyme linked immunosorbent assay (ELISA) manifested that compound 5 suppressed migration and invasion of NSCLC cells by suppressing the nuclear factor κB (NF-κB) and the consequently decreased Matrix Metalloproteinase-9(MMP-9) secretion. Moreover, drug affinity responsive target stability (DARTS) experiment and molecular simulations confirmed that compound 5 was capable of binding with CCR1/CCR3/CCR5, and Van der Waals forces were instrumental in the binding process. Ile91, Tyr113, Gln284, and Ser184(CCR1-ligand5), Ile189, Met213, and Leu209(CCR3-ligand5), Phe109, Gln194, and Thr195(CCR5-ligand5) had Van der Waals interactions with ligand 5. Dynamic cross-correlation matrix (DCCM) and free energy landscape (FEL) showed that compound 5 could stably bind to CCR1/CCR3/CCR5 to change conformation of the protein and the tendency of residue movements, leading to a persistent inhibitory effect. This study aimed to provide assistance in the rational design of common antagonists for CCR1, CCR3, and CCR5.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-024-11025-1","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0

Abstract

Non-Small Cell Lung Cancer (NSCLC) was one of the most prevalent forms of lung cancer. Due to its ease of invasion and migration, the five-year survival rate was relatively low. Therefore, new strategies for NSCLC treatment were needed. CC chemokine receptor 1/3/5 (CCR1/CCR3/CCR5), a member of the G-protein coupled receptor family, could promote the migration and invasion of NSCLC cells by binding to related chemokines. Consequently, targeting CCR1, CCR3 and CCR5 might prevent the progression of the disease. So far, no compound had been reported as a common antagonist for CCR1, CCR3, and CCR5. In this research, we utilized virtual screening and structural optimization to obtain compound 5, which effectively inhibited the migration and invasion of NSCLC cells. Meanwhile, Western Blot and Enzyme linked immunosorbent assay (ELISA) manifested that compound 5 suppressed migration and invasion of NSCLC cells by suppressing the nuclear factor κB (NF-κB) and the consequently decreased Matrix Metalloproteinase-9(MMP-9) secretion. Moreover, drug affinity responsive target stability (DARTS) experiment and molecular simulations confirmed that compound 5 was capable of binding with CCR1/CCR3/CCR5, and Van der Waals forces were instrumental in the binding process. Ile91, Tyr113, Gln284, and Ser184(CCR1-ligand5), Ile189, Met213, and Leu209(CCR3-ligand5), Phe109, Gln194, and Thr195(CCR5-ligand5) had Van der Waals interactions with ligand 5. Dynamic cross-correlation matrix (DCCM) and free energy landscape (FEL) showed that compound 5 could stably bind to CCR1/CCR3/CCR5 to change conformation of the protein and the tendency of residue movements, leading to a persistent inhibitory effect. This study aimed to provide assistance in the rational design of common antagonists for CCR1, CCR3, and CCR5.

针对 CC 趋化因子受体 1/3/5 治疗非小细胞肺癌的新型小分子拮抗剂的鉴定和相互作用机制。
非小细胞肺癌(NSCLC)是最常见的肺癌形式之一。由于其易侵犯和迁移,五年生存率相对较低。因此,NSCLC 的治疗需要新的策略。CC趋化因子受体1/3/5(CCR1/CCR3/CCR5)是G蛋白偶联受体家族的成员,可通过与相关趋化因子结合促进NSCLC细胞的迁移和侵袭。因此,靶向 CCR1、CCR3 和 CCR5 可能会阻止疾病的发展。迄今为止,还没有化合物被报道为CCR1、CCR3和CCR5的共同拮抗剂。在这项研究中,我们利用虚拟筛选和结构优化获得了化合物5,它能有效抑制NSCLC细胞的迁移和侵袭。同时,Western Blot和酶联免疫吸附试验(ELISA)表明,化合物5通过抑制核因子κB(NF-κB),从而减少基质金属蛋白酶-9(MMP-9)的分泌,抑制了NSCLC细胞的迁移和侵袭。此外,药物亲和力反应靶标稳定性(DARTS)实验和分子模拟证实,化合物 5 能够与 CCR1/CCR3/CCR5 结合,范德华力在结合过程中起了重要作用。Ile91、Tyr113、Gln284 和 Ser184(CCR1-配体 5),Ile189、Met213 和 Leu209(CCR3-配体 5),Phe109、Gln194 和 Thr195(CCR5-配体 5)与配体 5 存在范德华相互作用。动态交叉相关矩阵(DCCM)和自由能谱(FEL)显示,配体5能稳定地与CCR1/CCR3/CCR5结合,改变蛋白质的构象和残基移动趋势,从而产生持续的抑制作用。该研究旨在为合理设计CCR1、CCR3和CCR5的常见拮抗剂提供帮助。
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
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信