Abstract
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.
Highlights
Protein arginine methyltransferases (PRMTs) transfer the methyl group from S-adenosyl-Lmethionine (SAM) to the guanidyl nitrogen atom of protein arginine, forming monomethylarginine and cofactor S-adenosyl-L-homocysteine (SAH) [1,2,3]
Sci. 2019, 20, 3840 of Protein arginine methyltransferase 1 (PRMT1) is composed of the SAM and substrate arginine binding sites
The results showed that the decreasing of asymmetrical dimethylarginine (ADMA) was because of the inhibition of PRMT1 rather than being metabolized by dimethylarginine dimethylaminohydrolases (DDAH), which indicated that the compound 9a influenced the PRMT-AMDA pathway
Summary
Protein arginine methyltransferases (PRMTs) transfer the methyl group from S-adenosyl-Lmethionine (SAM) to the guanidyl nitrogen atom of protein arginine, forming monomethylarginine (mMA) and cofactor S-adenosyl-L-homocysteine (SAH) [1,2,3]. PRMTs can catalyze protein arginine methylation and influence a wide range of cellular processes, including transcriptional regulation, RNA splicing, cell growth and differentiation [4,5]. According to their different biological characteristics, PRMTs are classified in three categories (Figure 1) [6]. A number of PRMT1 inhibitors have been reported (Figure 2). A number of PRMT1 inhibitors were reported, including RM65 [19], Stilbamidine [20], DB75 [21], Allantodapsone [20] and DCLX069 [22]. There is an urgent need to discover potent PRMT1 inhibitors
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