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The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695598/ https://www.ncbi.nlm.nih.gov/pubmed/31390828 http://dx.doi.org/10.3390/ijms20153840 |
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author | Sun, Yutong Wang, Zhe Yang, Hao Zhu, Xuanli Wu, Han Ma, Lu Xu, Fang Hong, Wei Wang, Hao |
author_facet | Sun, Yutong Wang, Zhe Yang, Hao Zhu, Xuanli Wu, Han Ma, Lu Xu, Fang Hong, Wei Wang, Hao |
author_sort | Sun, Yutong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6695598 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66955982019-09-05 The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors Sun, Yutong Wang, Zhe Yang, Hao Zhu, Xuanli Wu, Han Ma, Lu Xu, Fang Hong, Wei Wang, Hao Int J Mol Sci Article 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. MDPI 2019-08-06 /pmc/articles/PMC6695598/ /pubmed/31390828 http://dx.doi.org/10.3390/ijms20153840 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sun, Yutong Wang, Zhe Yang, Hao Zhu, Xuanli Wu, Han Ma, Lu Xu, Fang Hong, Wei Wang, Hao The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors |
title | The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors |
title_full | The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors |
title_fullStr | The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors |
title_full_unstemmed | The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors |
title_short | The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors |
title_sort | development of tetrazole derivatives as protein arginine methyltransferase i (prmt i) inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695598/ https://www.ncbi.nlm.nih.gov/pubmed/31390828 http://dx.doi.org/10.3390/ijms20153840 |
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