通过混合虚拟筛选发现新型 DJ-1 共价抑制剂。

IF 3.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Future medicinal chemistry Pub Date : 2024-04-01 Epub Date: 2024-02-23 DOI:10.4155/fmc-2023-0301

Yanyu Ma, Yidan Song, Junyi Wang, Xiayu Shi, Zhen Yuan, Shuang Li, Honglin Li, Zhuo Chen, Shiliang Li

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引用次数: 0

摘要

背景：DJ-1 是一种普遍表达的蛋白质，具有多种功能。DJ-1的过表达与多种癌症的发生有关，因此DJ-1有望成为癌症治疗的靶点。方法：为了寻找新型 DJ-1 抑制剂，我们采用了一种混合虚拟筛选策略，即在一个综合化合物库中结合基于结构和配体的虚拟筛选。结果硅学研究发现了六种潜在的 DJ-1 抑制剂，并在体外进行了细胞水平的评估。化合物 797780-71-3 在 ACHN 细胞中表现出抗增殖活性，IC50 值为 12.18 μM，并且能够抑制 Wnt 信号通路。这项研究发现了一种新型的 DJ-1 共价抑制剂，为进一步优化该化合物铺平了道路。

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Discovery of novel covalent inhibitors of DJ-1 through hybrid virtual screening.

Background: DJ-1 is a ubiquitously expressed protein with multiple functions. Its overexpression has been associated with the occurrence of several cancers, positioning DJ-1 as a promising therapeutic target for cancer treatment. Methods: To find novel inhibitors of DJ-1, we employed a hybrid virtual screening strategy that combines structure-based and ligand-based virtual screening on a comprehensive compound library. Results: In silico study identified six hit compounds as potential DJ-1 inhibitors that were assessed in vitro at the cellular level. Compound 797780-71-3 exhibited antiproliferation activity in ACHN cells with an IC₅₀ value of 12.18 μM and was able to inhibit the Wnt signaling pathway. This study discovers a novel covalent inhibitor for DJ-1 and paves the way for further optimization.

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来源期刊

Future medicinal chemistry CHEMISTRY, MEDICINAL-

CiteScore

5.80

自引率

2.40%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.