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Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.

Original publication




Journal article


J Med Chem

Publication Date





5270 - 5290


Animals, Catalytic Domain, Cell Line, Drug Design, Enzyme Assays, Humans, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Imidazoles, Indoleamine-Pyrrole 2,3,-Dioxygenase, Ligands, Mice, Models, Molecular, Protein Binding, Protein Conformation, Quantitative Structure-Activity Relationship, Quantum Theory, Static Electricity, Triazoles, Tryptophan Oxygenase