Identification of protoberberine alkaloids as novel histone methyltransferase G9a inhibitors by structure-based virtual screening

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. Graphical abstract: [Figure not available: see fulltext.].