Rational design of indoleamine 2,3-dioxygenase inhibitors.

Détails

ID Serval
serval:BIB_92C7A1770680
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Rational design of indoleamine 2,3-dioxygenase inhibitors.
Périodique
Journal of Medicinal Chemistry
Auteur(s)
Röhrig U.F., Awad L., Grosdidier A., Larrieu P., Stroobant V., Colau D., Cerundolo V., Simpson A.J., Vogel P., Van den Eynde B.J., Zoete V., Michielin O.
ISSN
1520-4804[electronic], 0022-2623[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
53
Numéro
3
Pages
1172-1189
Langue
anglais
Résumé
Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.
Mots-clé
Animals, Cell Proliferation/drug effects, Cells, Cultured, Drug Design, Enzyme Inhibitors/chemical synthesis, Enzyme Inhibitors/chemistry, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors, Kynurenine/metabolism, Mice, Models, Molecular, Small Molecule Libraries, Structure-Activity Relationship, Tryptophan/metabolism
Pubmed
Web of science
Création de la notice
25/08/2010 14:14
Dernière modification de la notice
03/03/2018 19:32
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