School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi, 16419, South Korea.
J Comput Aided Mol Des. 2018 Sep;32(9):917-928. doi: 10.1007/s10822-018-0156-4. Epub 2018 Aug 31.
The protein lysine methyltransferase G9a, which controls gene expression by epigenetic regulation of H3K9 methylation, is related to various human diseases, including cancer, drug addiction, and mental retardation. In recent years, genetic, biological, and physiological evidence has established G9a inhibitors as potential chemotherapeutic agents for cancer treatment. In this study, we identified protoberberine alkaloid pseudodehydrocorydaline (CT13) as a novel G9a inhibitor, by structure-based virtual screening of in-house library containing natural product compounds. The activity of CT13 was determined by biophysical analyses involving MALDI-TOF mass spectrometry and western blot analysis. CT13 showed selective inhibitory activity against G9a and suppressed the level of H3K9me2 in MCF7 human breast cancer cells. Molecular docking analysis suggested the binding mode of CT13 which occupies the binding site of histone H3 substrate. CT13 provides a novel scaffold for further development of analogous synthetic G9a inhibitors.
蛋白赖氨酸甲基转移酶 G9a 通过组蛋白 H3K9 甲基化的表观遗传调控控制基因表达，与包括癌症、药物成瘾和智力迟钝在内的各种人类疾病有关。近年来，遗传、生物和生理证据已经确定 G9a 抑制剂是癌症治疗的潜在化疗药物。在这项研究中，我们通过对包含天然产物化合物的内部文库进行基于结构的虚拟筛选，确定原小檗碱生物碱伪脱氢紫堇碱 (CT13) 是一种新型的 G9a 抑制剂。通过涉及 MALDI-TOF 质谱和western blot 分析的生物物理分析确定 CT13 的活性。CT13 对 G9a 表现出选择性抑制活性，并抑制 MCF7 人乳腺癌细胞中 H3K9me2 的水平。分子对接分析表明 CT13 的结合模式占据了组蛋白 H3 底物的结合位点。CT13 为进一步开发类似的合成 G9a 抑制剂提供了新的支架。
