title: Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition.
abstract: 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.
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Ute F
authors.initials: UF
authors.lastname: Röhrig
authors.forename: Somi Reddy
authors.initials: SR
authors.lastname: Majjigapu
authors.forename: Aurélien
authors.initials: A
authors.lastname: Grosdidier
authors.forename: Sylvian
authors.initials: S
authors.lastname: Bron
authors.forename: Vincent
authors.initials: V
authors.lastname: Stroobant
authors.forename: Luc
authors.initials: L
authors.lastname: Pilotte
authors.forename: Didier
authors.initials: D
authors.lastname: Colau
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogel
authors.forename: Benoît J
authors.initials: BJ
authors.lastname: Van den Eynde
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D015195:Drug Design; D057075:Enzyme Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D055672:Static Electricity; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors
chemical_list: D007093:Imidazoles; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008024:Ligands; D014230:Triazoles; D014366:Tryptophan Oxygenase