Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation

Juxian Wang, Limin Chen, Sarmistha Halder Sinha, Zhongjie Liang, Huifang Chai, Sakthivel Muniyan, Yu Wei Chou, Chao Yang, Leilei Yan, You Feng, Keqin Kathy Li, Ming Fong Lin, Hualiang Jiang, Yujun George Zheng, Cheng Luo

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Protein arginine methyltransferases (PRMTs) are proved to play vital roles in chromatin remodeling, RNA metabolism, and signal transduction. Aberrant regulation of PRMT activity is associated with various pathological states such as cancer and cardiovascular disorders. Development and application of small molecule PRMT inhibitors will provide new avenues for therapeutic discovery. The combination of pharmacophore-based virtual screening methods with radioactive methylation assays provided six hits identified as inhibitors against the predominant arginine methyltransferase PRMT1 within micromolar potency. Two potent compounds, A9 and A36, exhibited the inhibitory effect by directly targeting substrate H4 other than PRMT1 and displayed even higher inhibition activity than the well-known PRMT inhibitors AMI-1. A9 significantly inhibits proliferation of castrate-resistant prostate cancer cells. Together, A9 may be a potential inhibitor against advanced hormone-independent cancers, and the work will provide clues for the future development of specific compounds that block the interaction of PRMTs with their targets.

Original languageEnglish (US)
Pages (from-to)7978-7987
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number18
StatePublished - Sep 27 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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