7K13

ACMSD in complex with diflunisal derivative 14

Summary for 7K13

• Entry DOI: 10.2210/pdb7k13/pdb
• Descriptor: 2-amino-3-carboxymuconate 6-semialdehyde decarboxylase, ZINC ION, 2-hydroxy-5-(thiophen-3-yl)benzoic acid, ... (4 entities in total)
• Functional Keywords: fda-approved drugs, nad+, neuropsychiatric disorders, decarboxylase, lyase
• Biological source: Pseudomonas fluorescens
• Total number of polymer chains: 3
• Total formula weight: 119568.47

Authors

Yang, Y.,Liu, A. (deposition date: 2020-09-07, release date: 2021-01-13, Last modification date: 2023-10-18)

Primary citation

Yang, Y.,Borel, T.,de Azambuja, F.,Johnson, D.,Sorrentino, J.P.,Udokwu, C.,Davis, I.,Liu, A.,Altman, R.A.
Diflunisal Derivatives as Modulators of ACMS Decarboxylase Targeting the Tryptophan-Kynurenine Pathway.
J.Med.Chem., 64:797-811, 2021

PubMed Abstract: In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD levels. In this study, an Food and Drug Administration (FDA)-approved drug, diflunisal, was found to competitively inhibit ACMSD. The complex structure of ACMSD with diflunisal revealed a previously unknown ligand-binding mode and was consistent with the results of inhibition assays, as well as a structure-activity relationship (SAR) study. Moreover, two synthesized diflunisal derivatives showed half-maximal inhibitory concentration (IC) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 μM () and 3.10 ± 0.11 μM (), respectively. The results suggest that diflunisal derivatives have the potential to modulate NAD levels. The ligand-binding mode revealed here provides a new direction for developing inhibitors of ACMSD.

PubMed: 33369426
DOI: 10.1021/acs.jmedchem.0c01762

Experimental method

X-RAY DIFFRACTION (1.83 Å)