7WMT

Crystal structure of small molecule 13 bound to human Nicotinamide N-methyltransferase

Summary for 7WMT

• Entry DOI: 10.2210/pdb7wmt/pdb
• Descriptor: Nicotinamide N-methyltransferase, [(2~{R},4~{S})-4-[2-(aminomethyl)imidazol-1-yl]-2-[1-[(4-chlorophenyl)methyl]-5-methyl-indol-2-yl]pyrrolidin-1-yl]-(1~{H}-pyrrolo[2,3-b]pyridin-5-yl)methanone (3 entities in total)
• Functional Keywords: nicotinamide n-methyltransferase, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 28247.85

Authors

Yoshida, S.,Uehara, S.,Kondo, N.,Takahashi, Y.,Yamamoto, S.,Kameda, A.,Kawagoe, S.,Inoue, N.,Yamada, M.,Yoshimura, N.,Tachibana, Y. (deposition date: 2022-01-17, release date: 2022-08-31, Last modification date: 2024-05-29)

Primary citation

Yoshida, S.,Uehara, S.,Kondo, N.,Takahashi, Y.,Yamamoto, S.,Kameda, A.,Kawagoe, S.,Inoue, N.,Yamada, M.,Yoshimura, N.,Tachibana, Y.
Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides.
J.Med.Chem., 65:10655-10673, 2022

PubMed Abstract: Recent 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 peptide display screening followed by pharmacophore-guided design of small molecules, and demonstrate the applicability using nicotinamide -methyltransferase (NNMT) as a target. Affinity selection by peptide display technology identified macrocyclic peptide that exhibited good enzymatic inhibitory activity but no cell-based activity. Thereafter, a peptide pharmacophore-guided design and further structure-based optimization resulted in highly potent and cell-active small molecule (cell-free IC = 0.0011 μM, cell-based IC = 0.40 μM), indicating that this strategy could be a new option for drug discovery.

PubMed: 35904556
DOI: 10.1021/acs.jmedchem.2c00919

Experimental method

X-RAY DIFFRACTION (1.77 Å)