Structural highlights
Function[NNMT_HUMAN] Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds. Publication Abstract from PubMedRecent technological innovations have led to the development of methods for the rapid identification of high-affinity macrocyclic peptides for a wide range of targets; however, it is still challenging to achieve the desired activity and membrane permeability at the same time. Here, we propose a novel small molecule lead discovery strategy, Peptide-to-Small Molecule, which is a combination of rapid identification of high-affinity macrocyclic peptides via peptide display screening followed by pharmacophore-guided de novo design of small molecules, and demonstrate the applicability using nicotinamide N-methyltransferase (NNMT) as a target. Affinity selection by peptide display technology identified macrocyclic peptide 1 that exhibited good enzymatic inhibitory activity but no cell-based activity. Thereafter, a peptide pharmacophore-guided de novo design and further structure-based optimization resulted in highly potent and cell-active small molecule 14 (cell-free IC50 = 0.0011 muM, cell-based IC50 = 0.40 muM), indicating that this strategy could be a new option for drug discovery. Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides.,Yoshida S, Uehara S, Kondo N, Takahashi Y, Yamamoto S, Kameda A, Kawagoe S, Inoue N, Yamada M, Yoshimura N, Tachibana Y J Med Chem. 2022 Aug 11;65(15):10655-10673. doi: 10.1021/acs.jmedchem.2c00919., Epub 2022 Jul 29. PMID:35904556[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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This page was last modified 19:31, 7 September 2022.