Rational design of indoleamine 2,3-dioxygenase inhibitors

Röhrig, Ute F.;Awad, Loay;Grosdidier, Aurélien;Larrieu, Pierre;Michielin, Olivier;et.al.
(2010) Journal of Medicinal Chemistry — Vol. 53, n° 3, p. 1172-1189 (2010)

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Authors
  • Röhrig, Ute F.LICR Lausanne & Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland
    Author
  • Awad, LoayLICR Lausanne & Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Author
  • Grosdidier, AurélienSwiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland
    Author
  • Larrieu, PierreUCLouvain
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  • Stroobant, VincentUCLouvain
    Author
  • Colau, DidierUCLouvain
    Author
  • Van den Eynde, Benoitorcid-logoUCLouvain
    Author
  • Michielin, OlivierLICR Lausanne & Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland
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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 or 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.
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Röhrig, U. F., Awad, L., Grosdidier, A., Larrieu, P., Stroobant, V., Colau, D., Cerundolo, V., Simpson, A. J. G., Vogel, P., Van den Eynde, B., Zoete, V., & Michielin, O. (2010). Rational design of indoleamine 2,3-dioxygenase inhibitors. Journal of Medicinal Chemistry, 53(3), 1172-1189. https://doi.org/10.1021/jm9014718 (Original work published 2010)