Inhibition of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by β-carboline and indole derivatives☆
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Indoleamine 2,3-dioxygenase
2023, Metalloenzymes: From Bench to BedsideDiverse chemical space of indoleamine-2,3-dioxygenase 1 (Ido1) inhibitors
2021, European Journal of Medicinal ChemistryIndoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor
2017, Toxicology and Applied PharmacologyTargeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy
2015, Drug Discovery TodayCitation Excerpt :Given the ‘promiscuous ligand binding site’ of the AhR [64], and evidence indicating AhR ligand-activated signalling leads to increased IDO1 expression [28], the prospect that structurally diverse IDO1, IDO2, and/or TDO inhibitors (e.g., Table 1) might also bind to the AhR, potentially counteracting their immunoregulatory effects, should be further investigated. Norharman (Table 1), for example, is a β-carboline-based inhibitor that has been shown to be effective against IDO1 (Ki 1280 ± 110 μM [16]), IDO2 (mouse Ki 690 ± 50 μM [16]), and TDO (mouse Ki 290 μM [65]). A simple, achiral molecule, norharman is hypothesised to bind directly to the heme centre of IDO1 as a nitrogen-donor ligand that competes with O2 rather than with tryptophan for the enzyme active site.
Exploring allosteric activation of LigAB from Sphingobium sp. strain SYK-6 through kinetics, mutagenesis and computational studies
2015, Archives of Biochemistry and BiophysicsCitation Excerpt :In mammalian cysteine dioxygenase, covalent modification of the enzyme by cysteine (the substrate) produces a non-allosteric activation which then effects an 11 – fold rate enhancement, but is not strictly required for activity [59]. In human indoleamine dioxygenase (IDO), activity (Vmax) is enhanced through binding of synthetic indole derivatives to an auxiliary binding pocket near the active site, leading to a 35–60% rate enhancement (depending upon the pH and effector molecule) [60–64]. Those studies suggested the existence of an auxiliary binding site for IDO allosteric effectors which was recently identified by computational docking studies using the IDO crystal structure [65].
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This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, and by grants from the Japanese Foundation on Metabolism and Diseases, Fujiwara Memorial Foundation, the Japan Heart Foundation and Shimadzu Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.