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 journalArticle

58 Citations (Scopus)

Abstract

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
Volume55
Issue number18
DOIs
StatePublished - Sep 27 2012

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Protein-Arginine N-Methyltransferases
Methylation
Arginine
Proteins
Chromatin Assembly and Disassembly
Signal Transduction
Neoplasms
Prostatic Neoplasms
Hormones
RNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. / Wang, Juxian; Chen, Limin; Sinha, Sarmistha Halder; Liang, Zhongjie; Chai, Huifang; Muniyan, Sakthivel; Chou, Yu Wei; Yang, Chao; Yan, Leilei; Feng, You; Kathy Li, Keqin; Lin, Ming-Fong; Jiang, Hualiang; George Zheng, Yujun; Luo, Cheng.

In: Journal of Medicinal Chemistry, Vol. 55, No. 18, 27.09.2012, p. 7978-7987.

Research output: Contribution to journalArticle

Wang, J, Chen, L, Sinha, SH, Liang, Z, Chai, H, Muniyan, S, Chou, YW, Yang, C, Yan, L, Feng, Y, Kathy Li, K, Lin, M-F, Jiang, H, George Zheng, Y & Luo, C 2012, 'Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation', Journal of Medicinal Chemistry, vol. 55, no. 18, pp. 7978-7987. https://doi.org/10.1021/jm300521m
Wang, Juxian ; Chen, Limin ; Sinha, Sarmistha Halder ; Liang, Zhongjie ; Chai, Huifang ; Muniyan, Sakthivel ; Chou, Yu Wei ; Yang, Chao ; Yan, Leilei ; Feng, You ; Kathy Li, Keqin ; Lin, Ming-Fong ; Jiang, Hualiang ; George Zheng, Yujun ; Luo, Cheng. / Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 18. pp. 7978-7987.
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AU - Yan, Leilei

AU - Feng, You

AU - Kathy Li, Keqin

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AU - George Zheng, Yujun

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