3 200 compounds
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing protein that catalyzes the oxidative cleavage of the C2−C3 double bond of the indole in tryptophan to provide N-formylkynurenine. Inhibition of this pathway is perspective and very attractive for the treatment of number of neurological disorders, such as Alzheimer’s disease, Parkinson’s disease and cerebral ischemia. In addition, overexpression of IDO1 has been reported in many tumor cells that lead to consideration of IDO1 as one of the key factors that contributes to cancer immunosuppression in tumor microenvironment.
Library Design
According to the literature data the key interaction of IDO-inhibitors is coordination to Fe-ion of the heme in the active site. Exactly this interaction with inhibitors prevents participation of Fe-ion in indole amine oxidation.
Significant number of the known IDO-inhibitors is hydrophilic compounds that have relatively low molecular weight. Therefore strict molecular parameters (lead-likeness, Veber rules) were applied for initial compound set selection. We have developed a holistic approach to the library design that includes ligand-/receptor-based virtual screening and enrichment with heme-binding fragments along with new chemotypes selection.
Ligand-based approach: Compounds with similar scaffolds, chemotypes and key moieties were picked out from our stock collection.
Docking: Virtual screening was carried out with heme coordination constraint and other important structural features that are specific for vast majority of potent ligands. The ability of ligands to fill the ambient sub-pockets was set as preferable.
Selection by Fragments: Critical search of molecules bearing fragments reported to form coordination bonds with heme. Compounds with unique chemotypes and appropriate shapes were included to the library.
Chelating fragments included in the library and examples of utilized reference compounds
Examples of compounds from IDO1 Library
