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Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase.

Persch E, Bryson S, Todoroff NK, Eberle C, Thelemann J, Dirdjaja N, Kaiser M, Weber M, Derbani H, Brun R, Schneider G, Pai EF, Krauth-Siegel RL, Diederich F
ChemMedChem 9 1880-91 (2014)
Cited: 24 times
EuropePMC logo PMID: 24788386

Abstract

The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called "mepacrine binding site". The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.

Reviews - 4new mentioned but not cited (2)

  1. Polyamines in protozoan pathogens. Phillips MA. J Biol Chem 293 18746-18756 (2018)
  2. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 E1389 (2016)

Articles - 4new mentioned but not cited (2)

  1. Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening. Turcano L, Torrente E, Missineo A, Andreini M, Gramiccia M, Di Muccio T, Genovese I, Fiorillo A, Harper S, Bresciani A, Colotti G, Ilari A. PLoS Negl Trop Dis 12 e0006969 (2018)
  2. Trypanocidal Mechanism of Action and in silico Studies of p-Coumaric Acid Derivatives. Lopes SP, Castillo YP, Monteiro ML, Menezes RRPPB, Almeida RN, Martins AMC, Sousa DP. Int J Mol Sci 20 E5916 (2019)


Reviews citing this publication (5)

  1. Molecular recognition in chemical and biological systems. Persch E, Dumele O, Diederich F. Angew Chem Int Ed Engl 54 3290-3327 (2015)
  2. Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs against Leishmaniasis and Trypanosomiases. Battista T, Colotti G, Ilari A, Fiorillo A. Molecules 25 E1924 (2020)
  3. Polyamine-trypanothione pathway: an update. Ilari A, Fiorillo A, Genovese I, Colotti G. Future Med Chem 9 61-77 (2017)
  4. An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases. Kourbeli V, Chontzopoulou E, Moschovou K, Pavlos D, Mavromoustakos T, Papanastasiou IP. Molecules 26 4629 (2021)
  5. Molecular insights into trypanothione reductase-inhibitor interaction: A structure-based review. Tiwari N, Tanwar N, Munde M. Arch Pharm (Weinheim) 351 e1700373 (2018)

Articles citing this publication (15)

  1. Tryparedoxin peroxidase-deficiency commits trypanosomes to ferroptosis-type cell death. Bogacz M, Krauth-Siegel RL. Elife 7 e37503 (2018)
  2. Trypanothione reductase: a target protein for a combined in vitro and in silico screening approach. Beig M, Oellien F, Garoff L, Noack S, Krauth-Siegel RL, Selzer PM. PLoS Negl Trop Dis 9 e0003773 (2015)
  3. Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors. Chacón-Vargas KF, Nogueda-Torres B, Sánchez-Torres LE, Suarez-Contreras E, Villalobos-Rocha JC, Torres-Martinez Y, Lara-Ramirez EE, Fiorani G, Krauth-Siegel RL, Bolognesi ML, Monge A, Rivera G. Molecules 22 E220 (2017)
  4. A tryparedoxin-coupled biosensor reveals a mitochondrial trypanothione metabolism in trypanosomes. Ebersoll S, Bogacz M, Günter LM, Dick TP, Krauth-Siegel RL. Elife 9 e53227 (2020)
  5. Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities. O'Sullivan MC, Durham TB, Valdes HE, Dauer KL, Karney NJ, Forrestel AC, Bacchi CJ, Baker JF. Bioorg Med Chem 23 996-1010 (2015)
  6. Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma. De Gasparo R, Brodbeck-Persch E, Bryson S, Hentzen NB, Kaiser M, Pai EF, Krauth-Siegel RL, Diederich F. ChemMedChem 13 957-967 (2018)
  7. Efficient Dimerization Disruption of Leishmania infantum Trypanothione Reductase by Triazole-phenyl-thiazoles. Revuelto A, de Lucio H, García-Soriano JC, Sánchez-Murcia PA, Gago F, Jiménez-Ruiz A, Camarasa MJ, Velázquez S. J Med Chem 64 6137-6160 (2021)
  8. Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase. Marcu A, Schurigt U, Müller K, Moll H, Krauth-Siegel RL, Prinz H. Eur J Med Chem 108 436-443 (2016)
  9. Natural Sesquiterpene Lactones of the 4,15-iso-Atriplicolide Type are Inhibitors of Trypanothione Reductase. Lenz M, Krauth-Siegel RL, Schmidt TJ. Molecules 24 E3737 (2019)
  10. Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3-PEX19 Interaction. Li M, Gaussmann S, Tippler B, Ott J, Popowicz GM, Schliebs W, Sattler M, Erdmann R, Kalel VC. Front Cell Dev Biol 9 737159 (2021)
  11. Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines. Sola I, Artigas A, Taylor MC, Gbedema SY, Pérez B, Clos MV, Wright CW, Kelly JM, Muñoz-Torrero D. Bioorg Med Chem Lett 24 5435-5438 (2014)
  12. Antiprotozoal investigation of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Atalantoflavone alters the mitochondrial membrane potential. Lemos da Silva LA, Höehr de Moraes M, Scotti MT, Scotti L, de Jesus Souza R, Nantchouang Ouete JL, Biavatti MW, Steindel M, Sandjo LP. Parasitology 146 849-856 (2019)
  13. Identification of potential trypanothione reductase inhibitors among commercially available β-carboline derivatives using chemical space, lead-like and drug-like filters, pharmacophore models and molecular docking. Rodríguez-Becerra J, Cáceres-Jensen L, Hernández-Ramos J, Barrientos L. Mol Divers 21 697-711 (2017)
  14. In Silico Exploration of the Trypanothione Reductase (TryR) of L. mexicana. Barrera-Téllez FJ, Prieto-Martínez FD, Hernández-Campos A, Martínez-Mayorga K, Castillo-Bocanegra R. Int J Mol Sci 24 16046 (2023)
  15. Parasitic Protozoans: Exploring the Potential of N,N'-Bis[2-(5-bromo-7-azabenzimidazol-1-yl)-2-oxoethyl]ethylene-1,3-Diamine and Its Cyclohexyl-1,2-diamine Analogue as TryR and Pf-DHODH Inhibitors. Oluwafemi KA, Oyeneyin OE, Babatunde DD, Agbaffa EB, Aigbogun JA, Odeja OO, Emmanuel AV. Acta Parasitol 68 807-819 (2023)


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