Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1).

Details

Serval ID
serval:BIB_D8CCFFB94292
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1).
Journal
Journal of medicinal chemistry
Author(s)
Röhrig U.F., Reynaud A., Majjigapu S.R., Vogel P., Pojer F., Zoete V.
ISSN
1520-4804 (Electronic)
ISSN-L
0022-2623
Publication state
Published
Issued date
10/10/2019
Peer-reviewed
Oui
Volume
62
Number
19
Pages
8784-8795
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway of tryptophan metabolism, which is involved in immunity, neuronal function, and aging. Its implication in pathologies such as cancer and neurodegenerative diseases has stimulated the development of IDO1 inhibitors. However, negative phase III clinical trial results of the IDO1 inhibitor epacadostat in cancer immunotherapy call for a better understanding of the role and the mechanisms of IDO1 inhibition. In this work, we investigate the molecular inhibition mechanisms of four known IDO1 inhibitors and of two quinones in detail, using different experimental and computational approaches. We also determine for the first time the X-ray structure of the highly efficient 1,2,3-triazole inhibitor MMG-0358. Based on our results and a comprehensive literature overview, we propose a classification scheme for IDO1 inhibitors according to their inhibition mechanism, which will be useful for further developments in the field.
Keywords
Crystallography, X-Ray, Density Functional Theory, Enzyme Inhibitors/chemistry, Enzyme Inhibitors/metabolism, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors, Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism, Molecular Conformation, Oximes/chemistry, Oximes/metabolism, Protein Binding, Quinones/chemistry, Quinones/metabolism, Recombinant Proteins/biosynthesis, Recombinant Proteins/chemistry, Recombinant Proteins/isolation & purification, Sulfonamides/chemistry, Sulfonamides/metabolism, Temperature, Triazoles/chemistry, Triazoles/metabolism
Pubmed
Web of science
Create date
13/10/2019 17:35
Last modification date
07/07/2020 5:20
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