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Design and synthesis of novel PRMT1 inhibitors and investigation of their binding preferences using molecular modelling.

Authors
  • Yang, Hao1
  • Ouyang, Yifan1
  • Ma, Hao2
  • Cong, Hui1
  • Zhuang, Chunlin3
  • Lok, Wun-Taai4
  • Wang, Zhe1
  • Zhu, Xuanli1
  • Sun, Yutong1
  • Hong, Wei5
  • Wang, Hao6
  • 1 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China. , (China)
  • 2 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China; School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China. , (China)
  • 3 School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China. , (China)
  • 4 School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan 750021, PR China. , (China)
  • 5 School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan 750021, PR China. Electronic address: [email protected] , (China)
  • 6 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, PR China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Oct 15, 2017
Volume
27
Issue
20
Pages
4635–4642
Identifiers
DOI: 10.1016/j.bmcl.2017.09.016
PMID: 28927791
Source
Medline
Keywords
License
Unknown

Abstract

Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-l-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2. The most potent PRMT1 inhibitor, compound 13d, was selected for molecular dynamic simulations to investigate binding poses. Based on the free energy calculations and structural analysis, we predicted that the ethylenediamine group would tightly bind to Asp84, and the trifluoromethyl group should occupy part of substrate arginine binding site, which is consistent with our original goal. Our results show for the first time that PRMT1 inhibitors can target the Asp84 binding site, which will be helpful for future drug discovery studies.

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