Rational Design of 4-Aryl-1,2,3-Triazoles for Indoleamine 2,3-Dioxygenase 1 Inhibition
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target 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.
Keywords: Gaussian-Basis Sets ; Correlated Molecular Calculations ; Tumoral Immune Resistance ; T-Cell Proliferation ; Tryptophan 2,3-Dioxygenase ; Catalyzed Synthesis ; Terminal Alkynes ; Click Chemistry ; Sodium-Azide ; Competitive Inhibitors
Record created on 2012-07-13, modified on 2016-08-09