Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition

J Med Chem. 2012 Jun 14;55(11):5270-90. doi: 10.1021/jm300260v. Epub 2012 May 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Imidazoles
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Ligands
  • Triazoles
  • Tryptophan Oxygenase