通过 DNA 编码文库筛选发现新型 ROCK2 ATP 竞争性抑制剂

IF 2.5 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chenhua Zhang , Yu-Chih Liu , Depu Wang , Yili Wang
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引用次数: 0

摘要

阿尔茨海默病(AD)等神经变性疾病因其对个人和整个社会的影响而备受关注。了解这些疾病背后的机制并开发有效的治疗策略至关重要。一个新出现的潜在治疗靶点是Rho相关含线圈蛋白激酶2(ROCK2),因为它的积累和活性与记忆丧失密切相关。在本报告中,我们介绍了最近发现的一种能够竞争性抑制 ROCK2 活性的新分子。这种分子是通过利用 DNA 编码文库 (DEL) 筛选平台发现的。在针对 ROCK2 进行筛选后,合成了一种非 DNA 化合物,并对其抑制特性、选择性、作用机制和结合模式分析进行了研究。通过筛选,化合物 CH-2 对 ROCK2 的 IC50 值为 28 nM,而对 ROCK1 的选择性为 5 倍。通过分子对接的进一步分析,我们深入了解了该化合物的特定结合模式。我们的研究结果表明,DEL 选择为确定新抑制剂提供了一种快速方法。其中,CH-2 化合物有望成为潜在的 ROCK2 抑制剂,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of a novel ROCK2 ATP competitive inhibitor by DNA-encoded library selection

Discovery of a novel ROCK2 ATP competitive inhibitor by DNA-encoded library selection

Discovery of a novel ROCK2 ATP competitive inhibitor by DNA-encoded library selection

Neurodegeneration disorders, such as Alzheimer's disease (AD), have garnered significant attention due to their impact on individuals and society as a whole. Understanding the mechanisms behind these disorders and developing effective therapy strategies is of utmost importance. One potential therapeutic target that has emerged is Rho-associated coiled-coil containing protein kinase 2 (ROCK2), as its accumulation and activity have been closely linked to memory loss. In this report, we present the findings of a recent discovery involving a new molecule that has the ability to competitively inhibit ROCK2 activity. This molecule was identified through the utilization of a DNA-encoded library (DEL) screening platform. Following selection against ROCK2, an off-DNA compound was synthesized and examined to ascertain its inhibitory properties, selectivity, mechanism of action, and binding mode analysis. From the screening, compound CH-2 has demonstrated an IC50 value of 28 nM against ROCK2, while exhibiting a 5-fold selectivity over ROCK1. Further analysis through molecular docking has provided insights into the specific binding modes of this compound. Our findings suggest that DEL selection offers a rapid method for identifying new inhibitors. Among these, the CH-2 compound shows promise as a potential ROCK2 inhibitor and warrants further investigation.

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来源期刊
Biochemical and biophysical research communications
Biochemical and biophysical research communications 生物-生化与分子生物学
CiteScore
6.10
自引率
0.00%
发文量
1400
审稿时长
14 days
期刊介绍: Biochemical and Biophysical Research Communications is the premier international journal devoted to the very rapid dissemination of timely and significant experimental results in diverse fields of biological research. The development of the "Breakthroughs and Views" section brings the minireview format to the journal, and issues often contain collections of special interest manuscripts. BBRC is published weekly (52 issues/year).Research Areas now include: Biochemistry; biophysics; cell biology; developmental biology; immunology ; molecular biology; neurobiology; plant biology and proteomics
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