Wang Shu-Qin, Wang Xinyu, Guo Lingling, Chen Xiao-Xia, Huang Xiao-Jun, Zhang Shiqing, Ye Wen-Cai, Zhang Xiao-Qi, Shi Lei, Wang Ying, Hu Li-Jun
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510632, People's Republic of China.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, Jinan University, Guangzhou 510632, People's Republic of China.
ACS Med Chem Lett. 2025 Mar 4;16(3):475-482. doi: 10.1021/acsmedchemlett.4c00635. eCollection 2025 Mar 13.
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 evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds and potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that and may stably bind to the eEF2K protein. Our findings highlighted and as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.
真核生物延伸因子2激酶（eEF2K）是一种非典型的丝氨酸/苏氨酸蛋白激酶，通过对eEF2进行抑制性磷酸化来调节神经元蛋白质合成稳态，已成为包括阿尔茨海默病（AD）在内的多种疾病的一个有前景的治疗靶点。在本研究中，我们利用分子对接方法，结合一个包含4270种化合物的内部天然产物库（其中有2177种新型化合物和603种新结构骨架）来鉴定eEF2K抑制剂。经过虚拟筛选，选择了25种天然产物来评估其对eEF2磷酸化的抑制作用以及对蛋白质合成的促进作用。我们的研究结果表明，化合物 和 能有效抑制eEF2K活性，增加蛋白质合成，并同时诱导神经突生长。分子动力学模拟表明， 和 可能与eEF2K蛋白稳定结合。我们的研究结果突出了 和 作为新型天然eEF2K抑制剂以及促进神经分化的有前景候选物的地位，为AD的治疗提供了潜在的治疗线索。
