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

Harshini Neelakantan, Hua Yu Wang, Virginia Vance, Jonathan Hommel, Stanton F. McHardy, Stanley Watowich

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)5015-5028
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number12
DOIs
StatePublished - Jun 22 2017

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Nicotinamide N-Methyltransferase
Structure-Activity Relationship
Inhibitory Concentration 50
Binding Sites
Ligands
Niacinamide
Drug Design
Metabolic Diseases
Xenobiotics
Enzymes
Methylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. / Neelakantan, Harshini; Wang, Hua Yu; Vance, Virginia; Hommel, Jonathan; McHardy, Stanton F.; Watowich, Stanley.

In: Journal of Medicinal Chemistry, Vol. 60, No. 12, 22.06.2017, p. 5015-5028.

Research output: Contribution to journalArticle

Neelakantan, Harshini ; Wang, Hua Yu ; Vance, Virginia ; Hommel, Jonathan ; McHardy, Stanton F. ; Watowich, Stanley. / Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 12. pp. 5015-5028.
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