Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step kynurenine pathway tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use anti-cancer immunotherapy. Lead optimization direct iron-binding has proven difficult due to remarkable selectivity sensitivity heme-ligand interactions. Here, we present experimental data a set closely related small azole compounds more than 4 orders magnitude differences their inhibitory activities, ranging from millimolar nanomolar levels. We investigate rationalize activities based on structural data, molecular dynamics simulations, density functional theory calculations. Our results not only expand presently known four confirmed sub-micromolar binding by two additional scaffolds but also provide model predict novel scaffolds.