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Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening

Abstract

We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic α/β-hydrolase domain and a β-propeller domain, and in which the substrate docks at the inter-domain interface, suggesting a “jaw opening” gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays. This strategy was successful as all 13 tested molecules suggested from the in silico calculations were found out to be active POPTc80 inhibitors in the micromolar range (lowest K i at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.

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Acknowledgments

This work was supported by CAPES-COFECUB N°723/11, CNPq, MCTI/CNPq/FNDCT/PRO-CENTRO-OESTE 407730/2013-3, FAPDF, FINEP and the Grant N°1891.7 between CNRS and CNPq. We thank the MBI project at LORIA for computer facilities.

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Correspondence to Bernard Maigret or Izabela Marques Dourado Bastos.

Additional information

Hugo de Almeida and Vincent Leroux have contributed equally to this work.

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Cite this article

de Almeida, H., Leroux, V., Motta, F.N. et al. Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening. J Comput Aided Mol Des 30, 1165–1174 (2016). https://doi.org/10.1007/s10822-016-9985-1

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Keywords

  • Chagas disease
  • Trypanosoma cruzi
  • Prolyl oligopeptidase
  • POPTc80
  • Homology modeling
  • Catalytic mechanism
  • Binding assays
  • Structure-based drug design
  • Virtual screening
  • Docking
  • GOLD
  • Molecular dynamics
  • NAMD