title: Rational design of indoleamine 2,3-dioxygenase inhibitors.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, Lausanne Branch, CH-1015 Lausanne, Switzerland.
authors.forename: Ute F
authors.initials: UF
authors.lastname: Röhrig
authors.forename: Loay
authors.initials: L
authors.lastname: Awad
authors.forename: Aurélien
authors.initials: A
authors.lastname: Grosdidier
authors.forename: Pierre
authors.initials: P
authors.lastname: Larrieu
authors.forename: Vincent
authors.initials: V
authors.lastname: Stroobant
authors.forename: Didier
authors.initials: D
authors.lastname: Colau
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
authors.forename: Andrew J G
authors.initials: AJ
authors.lastname: Simpson
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogel
authors.forename: Benoît J
authors.initials: BJ
authors.lastname: Van den Eynde
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D007737:Kynurenine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D054852:Small Molecule Libraries; D007737:Kynurenine; D014364:Tryptophan