Identification of PRMT5 inhibitors with novel scaffold structures through virtual screening and biological evaluations
- 10 June 2022
- journal article
- research article
- Published by Springer Nature in Journal of Molecular Modeling
- Vol. 28 (7) , 1-9
Abstract
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 IC50 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.Keywords
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Funding Information
- National Natural Science Foundation of China (81803339)
- Jiaxing Science and Technology Project (2018AY32002)
This publication has 36 references indexed in Scilit:
- Crystal structure of the human PRMT5:MEP50 complexProceedings of the National Academy of Sciences, 2012
- Growing PAINS in Academic Drug DiscoveryFuture Medicinal Chemistry, 2011
- Histone arginine methylationFEBS Letters, 2010
- Arginine methylation mediated by the Arabidopsis homolog of PRMT5 is essential for proper pre-mRNA splicingProceedings of the National Academy of Sciences, 2010
- Functional involvement of Tudor and dPRMT5 in the piRNA processing pathway in Drosophila germlinesThe EMBO Journal, 2009
- Protein Arginine Methylation in Mammals: Who, What, and WhyMolecular Cell, 2009
- The Amber biomolecular simulation programsJournal of Computational Chemistry, 2005
- Development and testing of a general amber force fieldJournal of Computational Chemistry, 2004
- Insights into Protein–Protein Binding by Binding Free Energy Calculation and Free Energy Decomposition for the Ras–Raf and Ras–RalGDS ComplexesJournal of Molecular Biology, 2003
- Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validationJournal of Computational Chemistry, 2002