Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Details

Serval ID
serval:BIB_3FC8F8F2B6EC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.
Journal
Journal of medicinal chemistry
Author(s)
Röhrig U.F., Majjigapu S.R., Reynaud A., Pojer F., Dilek N., Reichenbach P., Ascencao K., Irving M., Coukos G., Vogel P., Michielin O., Zoete V.
ISSN
1520-4804 (Electronic)
ISSN-L
0022-2623
Publication state
Published
Issued date
25/02/2021
Peer-reviewed
Oui
Volume
64
Number
4
Pages
2205-2227
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.
Pubmed
Web of science
Create date
22/02/2021 15:15
Last modification date
08/05/2021 6:32
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