Journal of Computer-Aided Molecular Design

, Volume 30, Issue 12, pp 1165–1174

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

  • Hugo de Almeida
  • Vincent Leroux
  • Flávia Nader Motta
  • Philippe Grellier
  • Bernard Maigret
  • Jaime M. Santana
  • Izabela Marques Dourado Bastos
Article

DOI: 10.1007/s10822-016-9985-1

Cite this article as:
de Almeida, H., Leroux, V., Motta, F.N. et al. J Comput Aided Mol Des (2016) 30: 1165. doi:10.1007/s10822-016-9985-1
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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 Ki at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.

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 

Supplementary material

10822_2016_9985_MOESM1_ESM.pdf (8.4 mb)
Supplementary material 1 (PDF 8592 kb)

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Hugo de Almeida
    • 1
  • Vincent Leroux
    • 2
  • Flávia Nader Motta
    • 1
    • 3
  • Philippe Grellier
    • 4
  • Bernard Maigret
    • 2
  • Jaime M. Santana
    • 1
  • Izabela Marques Dourado Bastos
    • 1
  1. 1.Department of Cellular Biology, Laboratory of Host-Pathogen InterfaceThe University of BrasíliaBrasíliaBrazil
  2. 2.LORIA, CNRS UMR 7503, INRIA Grand Est, CAPSID teamUniversity of LorraineVandœuvre-lès-NancyFrance
  3. 3.Faculty of CeilândiaThe University of BrasíliaBrasíliaBrazil
  4. 4.UMR 7245 CNRS, Équipe APE, CP52Muséum National d’Histoire NaturelleParisFrance

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