鉴定,实验验证,并通过分层虚拟筛选潜在的ALK抑制剂的计算评估。

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Y K Zhang, J B Tong, M X Luo, J Y Zhao, Y L Yang, Y Sun, Z P Qing
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引用次数: 0

摘要

间变性淋巴瘤激酶(ALK)在恶性肿瘤如非小细胞肺癌、淋巴瘤和神经母细胞瘤的发生和发展中起着关键的致癌作用。ALK基因突变或重排可显著增强肿瘤细胞的增殖和存活。然而,在临床环境中对现有ALK抑制剂的耐药性的出现仍然是一个主要挑战。因此,针对alk耐药突变的下一代抑制剂的开发已成为抗癌药物发现领域的中心焦点。在这项研究中,基于蛋白质结构的分层虚拟筛选策略被用于筛选Topscience药物样数据库中50,000种化合物的87,454种配体构象。结构聚类分析和ADMET药物相似性预测鉴定出两种潜在的ALK抑制剂F6524-1593和F2815-0802。随后的活性验证、分子对接和分子动力学模拟阐明了它们潜在的结合模式和作用机制。该研究为开发针对耐药突变的新型ALK抑制剂提供了有价值的理论见解,并为优化ALK靶向治疗策略提供了指导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification, experimental validation, and computational evaluation of potential ALK inhibitors through hierarchical virtual screening.

Anaplastic Lymphoma Kinase (ALK) plays a pivotal oncogenic role in the onset and progression of malignancies such as non-small cell lung cancer, lymphoma, and neuroblastoma. ALK gene mutations or rearrangements significantly enhance tumour cell proliferation and survival. However, the emergence of resistance to existing ALK inhibitors in clinical settings remains a major challenge. Consequently, the development of next-generation inhibitors targeting ALK-resistant mutations has become a central focus in the field of anticancer drug discovery. In this study, a hierarchical virtual screening strategy based on protein structure was utilized to screen 87,454 ligand conformations from 50,000 compounds in the Topscience drug-like database. Structural clustering analysis and ADMET drug-likeness predictions led to the identification of two potential ALK inhibitors, F6524-1593 and F2815-0802. Subsequent activity validation, molecular docking, and molecular dynamics simulations elucidated their potential binding modes and mechanisms of action. This study provides valuable theoretical insights for the development of novel ALK inhibitors targeting drug-resistant mutations and offers guidance for optimizing ALK-targeted therapeutic strategies.

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来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
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