Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 12, Pages 5015-5028Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00389
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Funding
- Department of Defense Peer Reviewed Medical Research Program [PR141776]
- University of Texas Medical Branch Technology Commercialization Award
- CDMRP [794373, PR141776] Funding Source: Federal RePORTER
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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 similar to 1 mu M) 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.
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