Huang Shenzhen, Wang Xiang, Lin Guifeng, Cheng Jie, Chen Xiuli, Sun Weining, Xiang Rong, Yu Yamei, Li Linli, Yang Shengyong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy Chengdu Sichuan 610041 China
Department of Clinical Medicine, School of Medicine, Nankai University Tianjin 300071 China.
RSC Adv. 2019 Mar 22;9(16):9323-9330. doi: 10.1039/c9ra00458k. eCollection 2019 Mar 15.
The human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS), which is well known for its essential aminoacylation function in protein synthesis, has been shown to translocate to the nucleus and protect against DNA damage caused by external stimuli. Small molecules that can fit into the active site pocket of TyrRS are thought to affect the nuclear role. The exploitation of TyrRS inhibitors has attracted attention recently. In this investigation, we adopted a structure-based virtual screening strategy and subsequent structure-activity relationship analysis to discover new TyrRS inhibitors, and identified a potent compound 5,7-dihydroxy-6,8-bis((3-hydroxyphenyl)thio)-2-phenyl-4-chromen-4-one (compound 11, = 8.8 μM). In intact HeLa cells, this compound showed a protective effect against DNA damage. Compound 11 is a good lead compound for the further development of drugs against disorders caused by DNA damage.
人类酪氨酰转移核糖核酸（tRNA）合成酶（TyrRS），因其在蛋白质合成中至关重要的氨酰化功能而广为人知，现已证明它可转运至细胞核并抵御外部刺激引起的DNA损伤。据认为，能够契合TyrRS活性位点口袋的小分子会影响其在细胞核中的作用。最近，TyrRS抑制剂的开发引起了关注。在本研究中，我们采用基于结构的虚拟筛选策略及后续的构效关系分析来发现新型TyrRS抑制剂，并鉴定出一种强效化合物5,7-二羟基-6,8-双（（3-羟基苯基）硫基）-2-苯基-4-色原酮-4-酮（化合物11，IC₅₀ = 8.8 μM）。在完整的HeLa细胞中，该化合物对DNA损伤具有保护作用。化合物11是进一步开发针对DNA损伤所致疾病药物的良好先导化合物。
