21NJ
Crystal structure of compound 10 bound to human Nicotinamide N-methyltransferase
This is a non-PDB format compatible entry.
Summary for 21NJ
| Entry DOI | 10.2210/pdb21nj/pdb |
| Descriptor | Nicotinamide N-methyltransferase, (3~{S})-~{N}-(2-oxidanylidene-3~{H}-1,3-benzothiazol-7-yl)-1-(2-pyridin-2-ylethyl)piperidine-3-carboxamide (3 entities in total) |
| Functional Keywords | nicotinamide n-methyltransferase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 62325.44 |
| Authors | Yoshida, S.,Kondo, N.,Uehara, S.,Yoshimura, N.,Sako, Y.,Yamamoto, S.,Kitade, M.,Tachibana, Y. (deposition date: 2025-12-20, release date: 2026-03-11, Last modification date: 2026-04-29) |
| Primary citation | Yoshida, S.,Kondo, N.,Uehara, S.,Yoshimura, N.,Sako, Y.,Yamamoto, S.,Kitade, M.,Tachibana, Y. Structure-Based Drug Discovery of Non-SAM-Mimetic Bisubstrate Inhibitors against Nicotinamide N ‐Methyltransferase. Acs Med.Chem.Lett., 17:847-855, 2026 Cited by PubMed Abstract: Nicotinamide -methyltransferase (NNMT) has emerged as a regulator of cellular methylation, epigenetic remodeling, and energy homeostasis. Its aberrant expression has been implicated in cancer, metabolic disorders, and renal diseases. Although several NNMT inhibitors have been reported, most lack selectivity, cellular activity, or favorable pharmacokinetic properties. Here, we describe the discovery and optimization of a novel non-SAM-mimetic bisubstrate inhibitor of NNMT originating from high-throughput screening. Guided by structure-based design, systematic modifications of hit compound yielded lead compound with over 1000-fold improved potency (IC for compounds and = 10 μM and 0.0084 μM, respectively). Compound exhibited sub-micromolar cell-based activity and high selectivity for a subfamily of methyltransferases. In rodents, compound exhibited pronounced renal distribution and moderate bioavailability, while achieving dose-dependent renal NNMT inhibition in a renal fibrosis model. These results highlight compound as a promising probe and a starting point for NNMT-targeted drug discovery. PubMed: 41982718DOI: 10.1021/acsmedchemlett.5c00762 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
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