Virtual screening and biological evaluation of novel small molecular inhibitors against protein arginine methyltransferase 1 (PRMT1)
Virtual screening and biological evaluation of novel small molecular inhibitors against protein arginine methyltransferase 1 (PRMT1)
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新型蛋白精氨酸甲基转移酶1（PRMT1）小分子抑制剂的虚拟筛选和生物学评价
DOI：
10.1039/c4ob01591f
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发表时间：
2014
影响因子：
3.2
通讯作者：
Luo Cheng
中科院分区：
文献类型：
--
作者：
Xie Yiqian;Zhou Ran;Lian Fulin;Liu Yan;Chen Limin;Shi Zhe;Zhang Naixia;Zheng Mingyue;Shen Bairong;Jiang Hualiang;Liang Zhongjie;Luo Cheng
蛋白质精氨酸甲基化是一种常见的翻译后修饰，对多种生物学过程至关重要。蛋白质精氨酸甲基转移酶（PRMT）活性失调与癌症和其他严重疾病有关。因此，针对PRMT的小分子抑制剂具有巨大的治疗开发潜力。本文通过虚拟筛选和生物活性测定相结合的方法，鉴定了6个小分子化合物为PRMT1抑制剂。其中，化合物DCLX 069和DCLX 078与PRMT 1的结合亲和力通过T1ρ和饱和转移差（STD）NMR实验进一步验证。最重要的是，这两种化合物有效地阻断了乳腺癌、肝癌和急性髓性白血病细胞系的细胞增殖。分子对接模拟结合模式分析表明，两种抑制剂均占据SAM结合口袋发挥抑制作用。总之，我们的化合物丰富了作为PRMT1抑制剂的结构支架，并为进一步优化提供了线索。
Protein arginine methylation is a common post-translational modification which is crucial for a variety of biological processes. Dysregulation of protein arginine methyltransferases (PRMTs) activity has been implicated in cancer and other serious diseases. Thus, small molecule inhibitors against PRMT have great potential for therapeutic development. Herein, through the combination of virtual screening and bioassays, six small molecular compounds were identified as PRMT1 inhibitors. Amongst them, the binding affinity of compounds DCLX069 and DCLX078 with PRMT1 was further validated by T1ρ and saturation transfer difference (STD) NMR experiments. Most important of all, both compounds effectively blocked cell proliferation in breast cancer, liver cancer and acute myeloid leukemia cell lines. The binding mode analysis from molecular docking simulations theoretically indicated that both inhibitors occupied the SAM binding pocket to exert the inhibitory effect. Taken together, our compounds enriched the structural scaffolds as PRMT1 inhibitors and afforded clues for further optimization.