Identification of the potential Pan-CDK antagonists: tracing the path of virtual screening and inhibitory activity on lung cancer cells.

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-07-29 DOI:10.1007/s11030-024-10939-0
Jia-Hao Tao, Ping-Lang Ruan, Jun Zhang, Yong Zhou, Cha-Xiang Guan
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Abstract

Cyclin-dependent kinases (CDKs) are overexpressed in tumor cells, and their aberrant activation can promote the progression of non-small-cell lung cancer (NSCLC). We utilized structure-based virtual screening and experimental validation to screen for potential CDKs antagonists among TargetMol natural products. Molecular docking and molecular dynamics simulation results indicate that Dolastatin 10 exhibits strong interactions with multiple subtypes of CDKs (CDK1, CDK2, CDK3, CDK4, and CDK6), forming stable CDKs-Dolastatin 10 complex compounds. Furthermore, in vitro experiments demonstrate that Dolastatin 10 significantly inhibits the viability, migration, and invasion of H1299 cells in a concentration-dependent manner, arresting the cell cycle at the G2/M phase by inducing cell senescence. These findings suggest that Dolastatin 10 may serve as a potential CDKs antagonist deserving further investigation.

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鉴定潜在的 Pan-CDK 拮抗剂:追踪虚拟筛选路径和对肺癌细胞的抑制活性。
细胞周期蛋白依赖性激酶(CDKs)在肿瘤细胞中过度表达,其异常激活可促进非小细胞肺癌(NSCLC)的进展。我们利用基于结构的虚拟筛选和实验验证,在 TargetMol 天然产物中筛选出潜在的 CDKs 拮抗剂。分子对接和分子动力学模拟结果表明,多拉他汀 10 能与多种亚型 CDKs(CDK1、CDK2、CDK3、CDK4 和 CDK6)发生强相互作用,形成稳定的 CDKs-Dolastatin 10 复合物。此外,体外实验证明,多拉他汀 10 能以浓度依赖性方式显著抑制 H1299 细胞的活力、迁移和侵袭,并通过诱导细胞衰老使细胞周期停滞在 G2/M 期。这些发现表明,多拉他汀 10 可能是一种潜在的 CDKs 拮抗剂,值得进一步研究。
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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;
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