In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity.

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2025-03-04 eCollection Date: 2025-03-13 DOI:10.1021/acsmedchemlett.4c00635

Shu-Qin Wang, Xinyu Wang, Lingling Guo, Xiao-Xia Chen, Xiao-Jun Huang, Shiqing Zhang, Wen-Cai Ye, Xiao-Qi Zhang, Lei Shi, Ying Wang, Li-Jun Hu

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Abstract

Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ser/Thr-protein kinase that regulates neuronal protein synthesis homeostasis via an inhibitory phosphorylation of eEF2, has emerged as a promising therapeutic target for several diseases, including Alzheimer's disease (AD). In this study, we employed molecular docking with an in-house natural product library of 4270 compounds, containing 2177 novel compounds and 603 new structural frameworks, to identify eEF2K inhibitors. Following virtual screening, 25 natural products were selected for in-vitro evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds 17 and 23 potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that 17 and 23 may stably bind to the eEF2K protein. Our findings highlighted 17 and 23 as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.

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具有神经生成活性的新型天然eEF2K抑制剂的硅筛选发现。

真核延伸因子2激酶（eEF2K）是一种非典型的丝氨酸/丝氨酸蛋白激酶，通过eEF2的抑制磷酸化调节神经元蛋白合成的稳态，已成为包括阿尔茨海默病（AD）在内的几种疾病的有希望的治疗靶点。在这项研究中，我们采用分子对接的方法，与一个包含4270个化合物的天然产物库，其中包含2177个新化合物和603个新的结构框架，来鉴定eEF2K抑制剂。通过虚拟筛选，我们选择了25种天然产物进行体外eEF2磷酸化抑制和促进蛋白质合成的评估。我们的研究发现，化合物17和23能有效抑制eEF2K活性，增加蛋白质合成，同时诱导神经细胞发生。分子动力学模拟表明，17和23可以稳定地与eEF2K蛋白结合。我们的研究结果突出了17和23作为新的天然eEF2K抑制剂和促进神经分化的有希望的候选者，为治疗AD提供了潜在的治疗线索。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.