Open AccessDiflunisal Derivatives as Modulators of ACMS Decarboxylase Targeting the Tryptophan–Kynurenine Pathway
Author(s) -
Yu Yang,
Timothy Borel,
Francisco de Azambuja,
David K. Johnson,
Jacob P. Sorrentino,
Chinedum Udokwu,
Ian Davis,
Aimin Liu,
Ryan A. Altman
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01762
Subject(s) - diflunisal , chemistry , nad+ kinase , kynurenine , indoleamine 2,3 dioxygenase , quinolinic acid , biochemistry , tryptophan , kynurenine pathway , nicotinamide adenine dinucleotide , nicotinamide , quinolinate , stereochemistry , enzyme , pharmacology , amino acid , medicine
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 50 ) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 μM ( 22 ) and 3.10 ± 0.11 μM ( 20 ), 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.