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J Med Chem. 2017 Jun 22;60(12):5015-5028. doi: 10.1021/acs.jmedchem.7b00389. Epub 2017 Jun 12.

Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase.

Author information

1
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch , Galveston, Texas 77550 United States.
2
Department of Chemistry and Center for Innovative Drug Discovery, University of Texas at San Antonio , San Antonio, Texas 78249 United States.
3
Department of Pharmacology and Toxicology, University of Texas Medical Branch , Galveston, Texas 77550 United States.

Abstract

Nicotinamide N-methyltransferase (NNMT) is a fundamental cytosolic biotransforming enzyme that catalyzes the N-methylation of endogenous and exogenous xenobiotics. We have identified small molecule inhibitors of NNMT with >1000-fold range of activity and developed comprehensive structure-activity relationships (SARs) for NNMT inhibitors. Screening of N-methylated quinolinium, isoquinolinium, pyrididium, and benzimidazolium/benzothiazolium analogues resulted in the identification of quinoliniums as a promising scaffold with very low micromolar (IC50 ∼ 1 μM) NNMT inhibition. Computer-based docking of inhibitors to the NNMT substrate (nicotinamide)-binding site produced a robust correlation between ligand-enzyme interaction docking scores and experimentally calculated IC50 values. Predicted binding orientation of the quinolinium analogues revealed selective binding to the NNMT substrate-binding site residues and essential chemical features driving protein-ligand intermolecular interactions and NNMT inhibition. The development of this new series of small molecule NNMT inhibitors direct the future design of lead drug-like inhibitors to treat several metabolic and chronic disease conditions characterized by abnormal NNMT activity.

PMID:
28548833
DOI:
10.1021/acs.jmedchem.7b00389
[Indexed for MEDLINE]

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