蛋白质精氨酸甲基转移酶5
化学
苯并咪唑
虚拟筛选
对接(动物)
IC50型
结构-活动关系
酶
细胞毒性
生物化学
立体化学
甲基转移酶
甲基化
药物发现
体外
医学
护理部
有机化学
基因
作者
Ying Zhang,Kongkai Zhu,Juan Zhang,Jinhe Zhang,Zhiling Song,Xinlei Zhang,Shan-Kui Liu,Cheng‐Shi Jiang
标识
DOI:10.2174/1381612829666230215105046
摘要
Background: PRMT5 is a major enzyme responsible for the post-translational symmetric demethylation of protein arginine residues, which has been validated as an effective therapeutic target for cancer. Thus, many nucleoside-based PRMT5 inhibitors have been reported in the past year. Objective: To discover a novel series of non-nucleoside PRMT5 inhibitors through a molecular docking-based virtual screening approach. Methods: Our in-house compound library was virtually screened using the Glide program, identifying a new PRMT5 inhibitor 1. Based on the structural similarity of hit 1, a series of structure-oriented derivatives, including 3a-3e, 7a-7g, and 12a-12f, were synthesized and selected for the inhibitory activity evaluation against PRMT5, as well as cytotoxicity against MV4-11 cell. Results: The analogs 7a-7e with benzimidazole core exhibited potent PRMT5 inhibitory activities, with 7e displaying the most potent activity with an IC50 of 6.81 ± 0.12 μM. In the anti-proliferative assay, compound 7e showed a strong inhibitory effect on MV4-11 cell growth. Finally, the binding mode of 7e with PRMT5 was predicted to provide insights for further structural optimization. Conclusion: The newly discovered PRMT5 inhibitors have potential antitumor activity against MV4-11 cells. This work highlighted this series of 3-(1H-benzo[d]imidazol-2-yl)aniline derivatives as novel anti-cancer lead compounds targeting PRMT5, which were worthy of further investigation.
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