作者: Joaquim, Larissa ; Belle, Fernanda ; Metzker, Kiuanne Lino Lobo ; da Silva, Marina Goulart ; Mathias, Khiany ; Gava, Fernanda Frederico ; Lins, Elisa Mitkus Flores ; Alano, Carolina Giassi ; Bonfante, Sandra ; Machado, Richard Simon ; da Silva Lemos, Isabela ; Daros, Guilherme Cabreira ; Petronilho, Fabricia ; de Bitencourt, Rafael Mariano ; Danielski, Lucinéia Gainski ; Reus, Gislaine Zilli ; Bobinski, Franciane ; Streck, Emilio Luiz ; Matiola, Rafaela Tezza

Background:In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition.Objective:This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis.Methods:Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days.Results:Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified.Conclusion:In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.

2024-08-22·Journal of Medicinal Chemistry

Structural Insights into Protein-Inhibitor Interactions in Human Tryptophan Dioxygenase

Article

作者: Yeh, Syun-Ru ; Ishigami, Izumi ; Frédérick, Raphaël ; Geeraerts, Zachary ; Kozlova, Arina ; Lewis-Ballester, Ariel ; Mathieu, Caroline ; Pham, Khoa N.

Human tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two important targets in cancer immunotherapy. Extensive research has led to a large number of potent IDO inhibitors; in addition, 52 structures of IDO in complex with inhibitors with a wide array of chemical scaffolds have been documented. In contrast, progress in the development of TDO inhibitors has been limited. Only four structures of TDO in complex with competitive inhibitors that compete with the substrate L-tryptophan for binding to the active site have been reported to date. Here we systematically evaluated the structures of TDO in complex with competitive inhibitors with three types of pharmacophores, imidazo-isoindole, indole-tetrazole, and indole-benzotriazole. The comparative assessment of the protein-inhibitor interactions sheds new light into the structure-based design of enzyme-selective inhibitors.

2024-08-01·Computers in biology and medicine

Cheminformatics analysis of indoleamine and tryptophan 2,3-dioxygenase inhibitors: A descriptor and fingerprint based machine learning approach to disclose selectivity measures.

Article

作者: Valipour, Mehdi ; Irannejad, Hamid

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are attractive drug targets for cancer immunotherapy. After disappointing results of the epacadostat as a selective IDO inhibitor in phase III clinical trials, there is much interest in the development of the TDO selective inhibitors. In the current study, several data analysis methods and machine learning approaches including logistic regression, Random Forest, XGBoost and Support Vector Machines were used to model a data set of compounds retrieved from ChEMBL. Models based on the Morgan fingerprints revealed notable fragments for the selective inhibition of the IDO, TDO or both. Multiple fragment docking was performed to find the best set of bound fragments and their orientation in the space for efficient linking. Linking the fragments and optimization of the final molecules were accomplished by means of an artificial intelligence generative framework. Finally, selectivity of the optimized molecules was assessed and the top 4 lead molecules were filtered through PAINS, Brenk and NIH filters. Results indicated that phenyloxalamide, fluoroquinoline, and 3-bromo-4-fluroaniline confer selectivity towards the IDO inhibition. Correspondingly, 1-benzyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione was found to be an integral fragment for the selective inhibition of the TDO by constituting a coordination bond with the Fe atom of heme. In addition, furo[2,3-c]pyridine-2,3-diamine was found as a common fragment for inhibition of the both targets and can be used in the design of the dual target inhibitors of the IDO and TDO. The new fragments introduced here can be a useful building blocks for incorporation into the selective TDO or dual IDO/TDO inhibitors.

100 项与 TDO/IDO Inhibitor(Curadev Pharma Pvt Ltd.) 相关的药物交易

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