High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)
| Autor: | Brandon A. Wright, Samuel Carlson, Elizabeth May, Vincent Chu, Petr Kuzmic, Shilpa Rani, Joseph D. Panarese, Rachelle Gaudet, Matthew D. Shair, Sreekanth Dittakavi, Danny T. C. Huang, Rocco L. Policarpo, Saravanakumar Dhakshinamoorthy, Aimo Kannt, Ludovic Decultot |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
animal structures
Protein Conformation Nicotinamide N-methyltransferase 01 natural sciences Cofactor Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Alkanes Enzyme Stability Nicotinamide N-Methyltransferase Humans Enzyme Inhibitors health care economics and organizations 030304 developmental biology 0303 health sciences Nicotinamide biology Temperature food and beverages Slow binding Methyltransferase inhibitor 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Biochemistry chemistry Metabolic enzymes Alkynes Molecular mechanism biology.protein Molecular Medicine K562 Cells Protein Binding |
| Zdroj: | J Med Chem |
| Popis: | In this work, structure-based rational design led to the development of potent and selective alkynyl bisubstrate inhibitors of NNMT. The reported nicotinamide-SAM conjugate (named NS1) features an alkyne as a key design element that closely mimics the linear, 180° transition state geometry found in the NNMT-catalyzed SAM → NAM (nicotinamide) methyl transfer reaction. NS1 was synthesized as a single enantiomer and diastereomer in 14 steps and found to be a high-affinity, subnanomolar NNMT inhibitor. An X-ray co-crystal structure and structure-activity relationship (SAR) study revealed the unique ability of an alkynyl linker to span the methyl transfer tunnel of NNMT with ideal shape complementarity. The compounds reported in this work represent the most potent and selective NNMT inhibitors reported to date. The rational design principle described herein could potentially be extended to other methyltransferase enzymes. |
| Databáze: | OpenAIRE |
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