Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

Journal of Medicinal Chemistry
Nicolas BabaultJian Jin

Abstract

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-l-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays an important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6) and characterization of this inhibitor in biochemical, biophysical, kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-molecule inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future.

Citations

Mar 15, 2019·Organic & Biomolecular Chemistry·Marlene L RotheShaun M K McKinnie

Related Concepts

NNMT protein, human
Coenzymes
Enzyme Inhibitors
Structure-Activity Relationship
Crystallography, X-Ray
Nicotinamide N-Methyltransferase
Drug Prospecting
Molecular Docking Analysis
Methylation
Physiological Aspects

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