Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase
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 à 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.
Neelakantan, Harshini,Wang, Hua-Yu,Vance, Virginia,Hommel, Jonathan D.,McHardy, Stanton F.,Watowich, Stanley J.
p. 5015 - 5028
(2017/06/28)
IMIDAZO[4,5-B]QUINOLINE-DERIVATIVES AND THEIR USE AS NO-SYNTHASE INHIBITORS
The compounds of formula I In which R1, R2, R3 and A have the meanings as given In the description are novel effective INOS Inhibitors.
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Page 15
(2010/02/08)
Condensed heterocycles; XI. Synthesis of 1,2,5-thia(selena)diazolo[3,4-b]quinolines and 1,2,5-thia(selena)diazolo[3,4-h]quinolines
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Sharma,Kumari,Singh
p. 316 - 318
(2007/10/02)
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