Screening Approaches Towards Trypanothione Reductase

Mathias, Beig; Oellien, Frank; Krauth‐Siegel, R. Luise; Selzer, Paul M.

doi:10.1002/9783527670383.ch21

Cited by 6 publications

(6 citation statements)

References 76 publications

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“…Despite these research efforts the role of the nitro group concerning the activity of such compounds could not be explained yet. In silico modeling and analysis of binding modes of compound 1 to TR suggest a potential interaction of the nitro group with Asn339 and/or Arg354 of TR [ 27 ]. Although these analyses are artificial to a certain extent, they might give a hint that the nitro group plays an important role in the binding of the compounds to TR.…”

Section: Resultsmentioning

confidence: 99%

“…Although several crystal structures of TR are available, their applicability for common structure-based virtual screening campaigns is inappropriate compared to other druggable protein targets like proteases [ 20 ], [ 21 ], [ 22 ], [ 23 ] or kinases [ 24 ], [ 25 ], [ 26 ]. TR has a very wide and featureless active site with approximate dimensions of 15 x 15 x 20 Å ( Fig 2 ) [ 27 ], [ 28 ]. In addition, the mainly hydrophobic TS 2 binding site does not provide many directed interactions like hydrogen bonds.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, ligands can bind with many different binding modes all over the active site. As a consequence, in silico approaches like molecular docking or pharmacophore screening are not capable to identify a reasonable and correct binding conformation [ 19 ], [ 21 ], [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Trypanothione Reductase: A Target Protein for a Combined In Vitro and In Silico Screening Approach

Mathias¹,

Oellien²,

Garoff

et al. 2015

PLoS Negl Trop Dis

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With the goal to identify novel trypanothione reductase (TR) inhibitors, we performed a combination of in vitro and in silico screening approaches. Starting from a highly diverse compound set of 2,816 compounds, 21 novel TR inhibiting compounds could be identified in the initial in vitro screening campaign against T. cruzi TR. All 21 in vitro hits were used in a subsequent similarity search-based in silico screening on a database containing 200,000 physically available compounds. The similarity search resulted in a data set containing 1,204 potential TR inhibitors, which was subjected to a second in vitro screening campaign leading to 61 additional active compounds. This corresponds to an approximately 10-fold enrichment compared to the initial pure in vitro screening. In total, 82 novel TR inhibitors with activities down to the nM range could be identified proving the validity of our combined in vitro/in silico approach. Moreover, the four most active compounds, showing IC50 values of <1 μM, were selected for determining the inhibitor constant. In first on parasites assays, three compounds inhibited the proliferation of bloodstream T. brucei cell line 449 with EC50 values down to 2 μM.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Trypanothione Reductase: A Target Protein for a Combined In Vitro and In Silico Screening Approach

Mathias¹,

Oellien²,

Garoff

et al. 2015

PLoS Negl Trop Dis

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“…The trypanocidal activity of mostly non-metal based TR inhibitor was rather low due to the fact that the inhibition of TR should be higher than 95% to impair the parasite viability. Moreover, as shown by Beig and co-workers, the large trypanothione binding cavity between the two TR monomers makes it difficult to use the classical in silico approaches like HTD and target-based in silico screenings [80,81].…”

Section: Future Perspectivementioning

confidence: 98%

Structural Insights into the Enzymes of the Trypanothione Pathway: Targets for Antileishmaniasis Drugs

et al. 2013

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Leishmaniasis is a neglected disease that kills 60,000 people worldwide, and which is caused by the protozoa Leishmania. The enzymes of the trypanothione pathway: trypanothione synthetase-amidase, trypanothione reductase (TR) and tryparedoxin-dependent peroxidase are absent in human hosts, and are essential for parasite survival and druggable. The most promising target is trypanothione synthetase-amidase, which has been also chemically validated. However, the structural data presented in this review show that TR also should be considered as a good target. Indeed, it is strongly inhibited by silver- and gold-containing compounds, which are active against Leishmania parasites and can be used for the development of novel antileishmanial agents. Moreover, TR trypanothione-binding site is not featureless but contains a sub-pocket where inhibitors bind, potentially useful for the design of new lead compounds.

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“…El agrupamiento tiol presente en diversos complejos enzimáticos cumple un papel determinante en la reducción de las ROS, regulando en este proceso otras funciones celulares (11). En particular, en los miembros de la familia Trypanosomatidae existe un sistema a base de tripanotiona [T(S)2] que junto a la flavoenzima Tripanotiona Reductasa, proporcionan las condiciones adecuadas para su supervivencia (12).…”

Section: Nuevos Enfoques Terapéuticos Y Blancos Moleculares En Tripanunclassified

Leishmaniasis y Enfermedad de Chagas: Herramientas para Nuevos Enfoques en su Tratamiento

Garay

Diaz

Kayano

et al. 2019

Rev. Soc. cient. Parag.

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La Leishmaniasis y la Enfermedad de Chagas afectan a millones de personas en América Latina y en otras regiones del mundo, siendo las poblaciones rurales pobres y vulnerables las más afectadas. Aunque se han realizado esfuerzos conjuntos para el combate de estas enfermedades desatendidas, la combinación de diferentes factores como el tratamiento ineficiente, la falta de interés para invertir en la búsqueda de nuevas fuentes terapéuticas y el surgimiento de cepas de parásitos resistentes acaban complicando las perspectivas. Esta situación torna de vital importancia el desarrollo de nuevas estrategias que apunten a la identificación de moléculas con potencial aplicación en la terapia o que puedan ejercer un efecto sinérgico cuando se complementan con la quimioterapia actual. Uno de los enfoques propuestos para este fin consiste en la búsqueda de estos agentes basados en blancos farmacológicos presentes en los parásitos causantes de las citadas enfermedades. Entre estos blancos moleculares se encuentran las enzimas implicadas en vías esenciales del parásito, como la Tripanotiona Reductasa (TR), involucrada en el combate al estrés oxidativo generado por las especies reactivas de oxígeno producidas por macrófagos del huésped durante la infección. Una herramienta importante en la búsqueda de inhibidores para esta enzima puede ser encontrada a través de la aplicación de herramientas in silico, que resulta un método relativamente rápido y de bajo costo, el cual permite seleccionar moléculas con potencial a partir de una gran variedad de fuentes. Los ensayos basados en el tamizaje (“screening”) virtual permiten la selección de moléculas de forma racional, que mediante ensayos complementarios pueden dar lugar al surgimiento futuro de nuevos fármacos.

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Screening Approaches Towards Trypanothione Reductase

Cited by 6 publications

References 76 publications

Trypanothione Reductase: A Target Protein for a Combined In Vitro and In Silico Screening Approach

Trypanothione Reductase: A Target Protein for a Combined In Vitro and In Silico Screening Approach

Structural Insights into the Enzymes of the Trypanothione Pathway: Targets for Antileishmaniasis Drugs

Leishmaniasis y Enfermedad de Chagas: Herramientas para Nuevos Enfoques en su Tratamiento

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