Discovery and optimization of isoliquiritigenin as a death-associated protein kinase 1 inhibitor,European Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › Eur. J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery and optimization of isoliquiritigenin as a death-associated protein kinase 1 inhibitor
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-09-04 , DOI: 10.1016/j.ejmech.2024.116836
Takeshi Yokoyama ₁ , Kotono Hisatomi ₂ , Saki Oshima ₂ , Ichiro Tanaka ₃ , Takuya Okada ₂ , Naoki Toyooka ₂

Affiliation

Death-associated protein kinase 1 (DAPK1) is a phosphotransferase in the serine/threonine kinase family. Inhibiting DAPK1 is expected to be beneficial in treating Alzheimer's disease and protecting neuronal cells during cerebral ischemia. In this study, we demonstrated that the natural chalcone isoliquiritigenin inhibits DAPK1 in an ATP-competitive manner, and we synthesized halogen derivatives to amplify the inhibitory effect. Among the compounds tested, the chlorine, bromine, and iodine derivatives exhibited high DAPK1 inhibitory activity and binding affinity. Crystal structure analysis revealed that this improvement is attributable to the halogen atoms fitting well into the hydrophobic pocket formed by I77, L93, and I160. In particular, the chlorine derivative showed a significant enthalpic contribution to the interaction with DAPK1, suggesting its potential as a primary compound for new DAPK1 inhibitors.

中文翻译：

异甘草素作为死亡相关蛋白激酶 1 抑制剂的发现和优化

死亡相关蛋白激酶 1 （DAPK1）是丝氨酸/苏氨酸激酶家族中的一种磷酸转移酶。抑制 DAPK1 有望有益于治疗阿尔茨海默病和在脑缺血期间保护神经元细胞。在这项研究中，我们证明了天然查尔酮异甘素以 ATP 竞争性方式抑制 DAPK1，并且我们合成了卤素衍生物以放大抑制作用。在测试的化合物中，氯、溴和碘衍生物表现出高 DAPK1 抑制活性和结合亲和力。晶体结构分析表明，这种改进归因于卤素原子很好地拟合了由 I77、L93 和 I160 形成的疏水口袋。特别是，氯衍生物对与 DAPK1 的相互作用显示出显着的焓贡献，表明其作为新 DAPK1 抑制剂的主要化合物的潜力。

更新日期：2024-09-04

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南