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 Fragment-Based Lead Generation of 5-Phenyl-1H-pyrazole-3-carboxamide Derivatives as Leads for Potent Factor Xia Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2002 ◽  
Author(s):  
Qunchao Wei ◽  
Zhichao Zheng ◽  
Shijun Zhang ◽  
Xuemin Zheng ◽  
Fancui Meng ◽  
...  
Keyword(s):  
Binding Mode ◽  
Lead Discovery ◽  
Inhibitory Potency ◽  
Efficient Manner ◽  
Factor Xia ◽  
Anticoagulant Drug ◽  
Lead Generation ◽  
Potent Factor ◽  
Major Target

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors’ lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor3 to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1H-pyrazole-3-carboxamide derivatives with different P1, P1′ and P2′moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33μM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner.

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 Modified Penicillin Molecule with Carbapenem-Like Stereochemistry Specifically Inhibits Class C β-Lactamases

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Xuehua Pan ◽  
Yunjiao He ◽  
Tianfeng Chen ◽  
Kin-Fai Chan ◽  
Yanxiang Zhao
Keyword(s):  
Active Site ◽  
Binding Mode ◽  
Carboxyl Group ◽  
Hydrogen Atoms ◽  
Chemical Modifications ◽  
Inhibitory Potency ◽  
Current Collection ◽  
Class A ◽  
Lactam Ring ◽  
Class C

ABSTRACT Bacterial β-lactamases readily inactivate most penicillins and cephalosporins by hydrolyzing and “opening” their signature β-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D β-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by “grafting” carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-α hydroxyethyl moiety to replace the original 6-β aminoacyl group. MPC-1 selectively inhibits class C β-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is ∼2 to 5 times higher than that for clinically used β-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A β-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel β-lactamase inhibitors.

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

How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling

2015 ◽  
Vol 71 (4) ◽  
pp. 447-454 ◽  
Author(s):  
Andrea Carletta ◽  
Anaëlle Tilborg ◽  
Laurence Moineaux ◽  
Jérôme de Ruyck ◽  
Livia Basile ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Crystal Structures ◽  
Heme Oxygenase ◽  
Binding Mode ◽  
Docking Studies ◽  
Heme Oxygenase 1 ◽  
Inhibitory Potency ◽  
Single Crystal Structures ◽  
Heme Cofactor ◽  
Good Agreement

Heme oxygenase-1 (HO-1) inhibition is associated with antitumor activity. Imidazole-based analogues show effective and selective inhibitory potency of HO-1. In this work, five single-crystal structures of four imidazole-based compounds are presented, with an in-depth structural analysis. In order to study the influence of the conformation of the ligands on binding to protein, conformational data from crystallography are compared with quantum mechanics analysis and molecular docking studies. Molecular docking of imidazole-based analogues in the active site of HO-1 is in good agreement with the experimental structures. Inhibitors interact with the heme cofactor and a hydrophobic pocket (Met34, Phe37, Val50, Leu147 and Phe214) in the HO-1 binding site. An alternate binding mode can be hypothesized for some inhibitors in the series.

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

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
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