Molecular and biochemical characterization of novel glucokinases from Trypanosoma cruzi and Leishmania spp.

Cáceres, Ana J.; Quiñones, Wilfredo; Gualdrón, Melisa; Cordeiro, Artur T.; Avilán, Luisana; Michels, Paul A.M.; Concepción, Juan Luís

doi:10.1016/j.molbiopara.2007.08.007

Cited by 45 publications

(37 citation statements)

References 42 publications

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“…In the majority of cases, the conformations calculated for compounds are in agreement with the interactions 9 reported in different studies 8,12,13 . Nevertheless, the compounds 2d and 2e did not reproduce the typical interactions of an inhibitor of catPARP-1; related compounds 2f and 2e did not report the typical interactions with their substratum.…”

Section: Analysis Of Potential Candidate Targets For 2a-f Quinoxalinessupporting

confidence: 84%

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Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Estevez

Quiliano

Burguete

et al. 2011

Experimental Parasitology

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Two series of pyrazol and propenone quinoxaline derivatives were tested for parasiticidal activity (against amastigotes of Leishmania peruviana and trypomastigotes of Trypanosoma cruzi) and for toxicity against proliferative and non-proliferative cells. The pyrazol series was almost inactive against1,4-dioxide inhibited 50% of Leishmania growth at 8.9 µM with no impact against proliferative kidney cells and low toxicity against Thp-1 and murine macrophages. The compounds of the propenone series were moderately active against T. cruzi. Among them, 2 compounds were particularly interesting: (2E)-1-(7-Fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone, that showed a selective activity against proliferative cells (cancer and parasites), being inactive against normal murine peritoneal macrophages and (2E)-3-(3,4,5-Trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone that was only active against Leishmania and inactive against the other tested cells.Furthermore in silico studies were performed for ADME properties and docking studies, both series of compounds respected the Lipinski's rules and show linear correlation between tripanosomaticidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.3

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Section: Analysis Of Potential Candidate Targets For 2a-f Quinoxalinessupporting

confidence: 84%

“…Alternatively, we only found two T. cruzi kinases, resolved by X-ray (1.9 Å and 2.1 Å resolution), of Arginine Kinase and glucokinase respectively (PDB ID: 2j1q and 2q2r) 9,10 .…”

Section: General Considerationsmentioning

confidence: 96%

Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Estevez

Quiliano

Burguete

et al. 2011

Experimental Parasitology

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“…Polyclonal antisera against purified recombinant TcGALKs were raised in mice (TcGALK-1) and rabbit (TcGALK-2) as described by Cáceres et al [31]. Both antisera were stored at -20 ºC.…”

Section: Production Of Rabbit and Mouse Polyclonal Antisera Against Rmentioning

confidence: 99%

Trypanosoma cruzi contains two galactokinases; molecular and biochemical characterization

Lobo-Rojas

González-Marcano

Valera-Vera

et al. 2016

Parasitology International

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“…The inhibition of these enzymes appears to be a good strategy for targeting since glycolysis and the PPP should encounter a direct impact by functioning with lower metabolic flux. T. cruzi hexokinase ( Tc HxK) has higher activity and is found at a higher percentage than T. cruzi glucokinase ( Tc GlcK) in the parasite (28), it is currently proposed that Tc HxK is a potential drug target (16), but the status of Tc GlcK is unclear. Genetic validation by RNAi cannot be carried out in T. cruzi parasites due to a nonfunctional RNAi pathway (29, 30).…”

Section: Introductionmentioning

confidence: 99%

Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase

D'Antonio

Deinema

Kearns

et al. 2015

Molecular and Biochemical Parasitology

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Glucokinase and hexokinase from pathogenic protozoa Trypanosoma cruzi are potential drug targets for antiparasitic chemotherapy of Chagas’ disease. These glucose kinases phosphorylate D-glucose with co-substrate ATP and yields glucose 6-phosphate and are involved in essential metabolic pathways, such as glycolysis and the pentose phosphate pathway. An inhibitor class was conceived that is selective for T. cruzi glucokinase (TcGlcK) using structure-based drug design involving glucosamine having a linker from the C2 amino that terminates with a hydrophobic group either being phenyl, p-hydroxyphenyl, or dioxobenzo[b]thiophenyl groups. The synthesis and characterization for two of the four compounds are presented while the other two compounds were commercially available. Four high-resolution X-ray crystal structures of TcGlcK inhibitor complexes are reported along with enzyme inhibition constants (Ki) for TcGlcK and Homo sapiens hexokinase IV (HsHxKIV). These glucosamine analogue inhibitors include three strongly selective TcGlcK inhibitors and a fourth inhibitor, benzoyl glucosamine (BENZ-GlcN), which is a similar variant exhibiting a shorter linker. Carboxybenzyl glucosamine (CBZ-GlcN) was found to be the strongest glucokinase inhibitor known to date, having a Ki of 0.71 ± 0.05 μM. Also reported are two biologically active inhibitors against in vitro Trypanosoma cruzi culture that were BENZ-GlcN and CBZ-GlcN, with intracellular amastigote growth inhibition IC50 values of 16.08 ± 0.16 μM and 48.73 ± 0.69 μM, respectively. These compounds revealed little to no toxicity against mammalian NIH-3T3 fibroblasts and provides a key starting point for further drug development with this class of compound.

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Molecular and biochemical characterization of novel glucokinases from Trypanosoma cruzi and Leishmania spp.

Cited by 45 publications

References 42 publications

Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Trypanosoma cruzi contains two galactokinases; molecular and biochemical characterization

Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase

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