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Open AccessArticle

The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors

by Yutong Sun 1,†, Zhe Wang 1,†, Hao Yang 1,†, Xuanli Zhu 1, Han Wu 1, Lu Ma 2, Fang Xu 3, Wei Hong 4,5,* and Hao Wang 1,*
1
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
2
School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
3
School of Postgraduate Education, Ningxia Medical University, Yinchuan 750004, China
4
School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan 750021, China
5
Key Laboratory of Chemical Engineering and Technology, State Ethnic Affairs Commission, North Minzu University, Yinchuan 750021, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(15), 3840; https://doi.org/10.3390/ijms20153840
Received: 27 June 2019 / Revised: 1 August 2019 / Accepted: 1 August 2019 / Published: 6 August 2019
(This article belongs to the Section Molecular Pharmacology)
Protein arginine methyltransferase 1 (PRMT1) can catalyze protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes. The dysregulation of PRMT1 is involved in a diverse range of diseases, including cancer. Therefore, there is an urgent need to develop novel and potent PRMT1 inhibitors. In the current manuscript, a series of 1-substituted 1H-tetrazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and five compounds demonstrated significant inhibitory effects against PRMT1. The most potent PRMT1 inhibitor, compound 9a, displayed non-competitive pattern with respect to either SAM or substrate arginine, and showed the strong selectivity to PRMT1 compared to PRMT5, which belongs to the type II PRMT family. It was observed that the compound 9a inhibited the functions of PRMT1 and relative factors within this pathway, and down-regulated the canonical Wnt/β-catenin signaling pathway. The binding of compound 9a to PRMT1 was carefully analyzed by using molecular dynamic simulations and binding free energy calculations. These studies demonstrate that 9a was a potent PRMT1 inhibitor, which could be used as lead compound for further drug discovery. View Full-Text
Keywords: PRMT1; structure-activity relationship (SAR); MOA studies; molecular dynamic simulations; binding mode PRMT1; structure-activity relationship (SAR); MOA studies; molecular dynamic simulations; binding mode
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MDPI and ACS Style

Sun, Y.; Wang, Z.; Yang, H.; Zhu, X.; Wu, H.; Ma, L.; Xu, F.; Hong, W.; Wang, H. The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors. Int. J. Mol. Sci. 2019, 20, 3840.

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