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J Med Chem ; 64(1): 797-811, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33369426

RESUMO

In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-ß-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 (IC50) 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.


Assuntos
Carboxiliases/metabolismo , Diflunisal/metabolismo , Inibidores Enzimáticos/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Vias Biossintéticas/efeitos dos fármacos , Carboxiliases/antagonistas & inibidores , Domínio Catalítico , Cristalografia por Raios X , Diflunisal/análogos & derivados , Diflunisal/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Cinurenina/metabolismo , Simulação de Acoplamento Molecular , NAD/metabolismo , Pseudomonas fluorescens/enzimologia , Relação Estrutura-Atividade , Triptofano/metabolismo
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