Rational Design of Indoleamine 2,3-Dioxygenase Inhibitors
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.
Keywords: Space Gaussian Pseudopotentials ; Human Dendritic Cells ; Tryptophan 2,3-Dioxygenase ; Immune Escape ; Competitive Inhibitors ; Coupling Reagents ; Major Reductant ; Drug Discovery ; Lead Discovery ; Exiguamine-A
Record created on 2011-12-16, modified on 2016-08-09