Identification of PRMT5 inhibitors with novel scaffold structures through virtual screening and biological evaluations.
Qian ZhangLun ZhangJia JinYaohua FanXiaoguang WangHaofeng HuXiaoqing YeLei WangChenxi CaoFei YePublished in: Journal of molecular modeling (2022)
Protein arginine methyltransferase 5 (PRMT5), an important member in PRMT family, has been validated as a promising anticancer target. In this study, through the combination of virtual screening and biological experiments, we have identified two PRMT5 inhibitors with novel scaffold structures. Among them, compound Y2431 showed moderate activity with IC 50 value of 10.09 μM and displayed good selectivity against other methyltransferases. The molecular docking analysis and molecular dynamics (MD) simulations suggested that the compound occupied the substrate-arginine binding site. Furthermore, Y2431 exhibited anti-proliferative activity to leukemia cells by inducing cell cycle arrest. Overall, the hit compound could provide a novel scaffold for further optimization of small-molecule PRMT5 inhibitors.
Keyphrases
- molecular dynamics
- cell cycle arrest
- molecular docking
- small molecule
- cell death
- pi k akt
- density functional theory
- tissue engineering
- nitric oxide
- amino acid
- high resolution
- induced apoptosis
- protein protein
- molecular dynamics simulations
- acute myeloid leukemia
- bone marrow
- signaling pathway
- high intensity
- cell proliferation
- mass spectrometry
- binding protein
- structural basis