title: Discovery and evaluation of inhibitors to the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1): Probing the active site-inhibitor interactions.
abstract: High expression of the immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) for a broad range of malignancies is associated with poor patient prognosis, and the enzyme is a validated target for cancer intervention. To identify novel IDO1 inhibitors suitable for drug development, 1597 compounds in the National Cancer Institute Diversity Set III library were tested for inhibitory activity against recombinant human IDO1. We retrieved 35 hits that inhibited IDO1 activity >50% at 20 μM. Five structural filters and the PubChem Bioassay database were used to guide the selection of five inhibitors with IC50between 3 and 12 μM for subsequent experimental evaluation. A pyrimidinone scaffold emerged as being the most promising. It showed excellent cell penetration, negligible cytotoxicity and passed four out of the five structural filters applied. To evaluate the importance of Ser167 and Cys129 residues in the IDO1 active site for inhibitor binding, the entire NCI library was subsequently screened against alanine-replacement mutant enzymes of these two residues. The results established that Ser167 but not Cys129 is important for inhibitory activity of a broad range of IDO1 inhibitors. Structure-activity-relationship studies proposed substituents interacting with Ser167 on four investigated IDO1 inhibitors. Three of these four Ser167 interactions associated with an increased IDO1 inhibition and were correctly predicted by molecular docking supporting Ser167 as an important mediator of potency for IDO1 inhibitors.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, New Zealand, Private Bag 92019, Victoria Street West, Auckland, New Zealand.
authors.forename: Petr
authors.initials: P
authors.lastname: Tomek
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, New Zealand, Private Bag 92019, Victoria Street West, Auckland, New Zealand.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, New Zealand, Private Bag 92019, Victoria Street West, Auckland, New Zealand.
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, New Zealand, Private Bag 92019, Victoria Street West, Auckland, New Zealand.
authors.forename: Chuanwen
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Raven
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, New Zealand, Private Bag 92019, Victoria Street West, Auckland, New Zealand. Electronic address: l.ching@auckland.ac.nz.
authors.forename: Lai-Ming
authors.initials: LM
authors.lastname: Ching
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009154:Mutation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase
keywords: Drug screening; IDO; Indoleamine 2,3-dioxygenase; Inhibitors; Molecular modeling; Mutagenesis