Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine-Conjugated Diaryl Sulfide Scaffolds

ChemMedChem ◽  
2009 ◽  
Vol 4 (12) ◽  
pp. 2034-2044 ◽  
Author(s):  
Christian Eberle ◽  
Johannes A. Burkhard ◽  
Bernhard Stump ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
...  
Keyword(s):  
Binding Mode ◽  
Trypanothione Reductase ◽  
Synthesis Inhibition ◽  
Inhibition Potency ◽  
Diaryl Sulfide

Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities

2008 ◽  
Vol 6 (21) ◽  
pp. 3935 ◽  
Author(s):  
Bernhard Stump ◽  
Christian Eberle ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
R. Luise Krauth-Siegel ◽  
...  
Keyword(s):  
Binding Mode ◽  
Trypanothione Reductase ◽  
Inhibition Potency ◽  
Diaryl Sulfide

Betraying the Parasite’s Redox System: Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties

ChemMedChem ◽  
2007 ◽  
Vol 2 (12) ◽  
pp. 1708-1712 ◽  
Author(s):  
Bernhard Stump ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
R. Luise Krauth-Siegel ◽  
François Diederich
Keyword(s):  
Redox System ◽  
Trypanothione Reductase ◽  
Diaryl Sulfide

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities

ChemMedChem ◽  
2010 ◽  
Vol 6 (2) ◽  
pp. 292-301 ◽  
Author(s):  
Christian Eberle ◽  
Birgit Sophia Lauber ◽  
Daniel Fankhauser ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
...  
Keyword(s):  
Binding Mode ◽  
Trypanothione Reductase ◽  
Inhibitory Potency

scholarly journals Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives

2017 ◽  
Vol 32 (1) ◽  
pp. 304-310 ◽  
Author(s):  
Francesco Saccoliti ◽  
Gabriella Angiulli ◽  
Giovanni Pupo ◽  
Luca Pescatori ◽  
Valentina Noemi Madia ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Diaryl Sulfide

scholarly journals 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases

2020 ◽  
Vol 13 (3) ◽  
pp. 52 ◽  
Author(s):  
Pasquale Linciano ◽  
Eleonora Gianquinto ◽  
Martina Montanari ◽  
Lorenzo Maso ◽  
Pierangelo Bellio ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Clinical Strains ◽  
Class A ◽  
Lactam Antibiotic ◽  
Inhibition Potency ◽  
In Silico Analyses

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available β-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of β-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine β−Lactamase (SBLs) KPC-2 and class B1 metallo β−Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent in silico analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems.

scholarly journals Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening

2018 ◽  
Vol 12 (11) ◽  
pp. e0006969 ◽  
Author(s):  
Lorenzo Turcano ◽  
Esther Torrente ◽  
Antonino Missineo ◽  
Matteo Andreini ◽  
Marina Gramiccia ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Reductase Inhibitor ◽  
Binding Mode ◽  
Trypanothione Reductase

scholarly journals Molecular Docking and Binding Mode Analysis of Plant Alkaloids as in Vitro and in silico Inhibitors of Trypanothione Reductase from Trypanosoma cruzi

2016 ◽  
Vol 11 (1) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Alonso J. Argüelles ◽  
Geoffrey A. Cordell ◽  
Helena Maruenda
Keyword(s):  
Molecular Docking ◽  
Trypanosoma Cruzi ◽  
Structural Diversity ◽  
Binding Mode ◽  
Mode Analysis ◽  
Trypanothione Reductase ◽  
Binding Interactions ◽  
Preferential Binding ◽  
Key Enzyme

Trypanothione reductase (TryR) is a key enzyme in the metabolism of Trypanosoma cruzi, the parasite responsible for Chagas disease. The available repertoire of TryR inhibitors relies heavily on synthetic substrates of limited structural diversity, and less on plant-derived natural products. In this study, a molecular docking procedure using a Lamarckian Genetic Algorithm was implemented to examine the protein-ligand binding interactions of strong in vitro inhibitors for which no X-ray data is available. In addition, a small, skeletally diverse, set of natural alkaloids was assessed computationally against T. cruzi TryR in search of new scaffolds for lead development. The preferential binding mode (low number of clusters, high cluster population), together with the deduced binding interactions were used to discriminate among the virtual inhibitors. This study confirms the prior in vitro data and proposes quebrachamine, cephalotaxine, cryptolepine, (22 S,25 S)-tomatidine, (22 R,25 S)-solanidine, and (22 R,25 R)-solasodine as new alkaloid scaffold leads in the search for more potent and selective TryR inhibitors.

scholarly journals Identification of novel thiadiazin derivatives as potentially selective inhibitors towards trypanothione reductase from Trypanosoma cruzi by molecular docking using the numerical index poses ratio Pr and the binding mode analysis

2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Julieta Coro-Bermello ◽  
Ernesto R. López-Rodríguez ◽  
Javier E. Alfonso-Ramos ◽  
Dayana Alonso ◽  
Gerardo M. Ojeda-Carralero ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Trypanosoma Cruzi ◽  
Ad Hoc ◽  
Binding Mode ◽  
Mode Analysis ◽  
Trypanothione Reductase ◽  
Binding Modes ◽  
Hybrid Ligands ◽  
Hydrophobic Cleft ◽  
Numerical Index

Abstract Chagas disease is a serious health problem in Central and South America for which effective treatment is not currently available. This illness is caused by the protozoa Trypanosoma cruzi, a species that relies on a thiol-based metabolism to regulate oxidative stress. Trypanothione reductase enzyme plays a central role in the metabolic pathway of the parasite. In this work, a virtual screening of a library of novel thiadiazine derivatives against trypanothione reductase using molecular docking was performed. Four different series of hybrid ligands having in the structure one or two peptoid moieties (series I and II) or the tetrazole ring (series III and IV) were considered. An ad hoc numerical index called poses ratio was introduced to interpret the results of the docking analysis and to establish relevant structure-interaction relationships. In addition, six binding modes were found for the ligands with the highest populated conformational clusters after applying contact-based analysis. The most regular and relevant were binding modes I and II, found mainly for ligands from series I. A subsequent molecular docking on human glutathione reductase enzyme allowed to assess the possible cytotoxicity of the ligands towards human cells. A selective binding profile was found for ligands with interactions in the Hydrophobic cleft, the spermidine and the Z subsites inside the active site of trypanothione reductase. At the end of the study, new thiadiazine-based compounds were identified as plausible candidates to selectively inhibit the parasitic enzyme. Graphic abstract

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