title: 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 Kiat 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.
authors: Department of Cellular Biology, Laboratory of Host-Pathogen Interface, The University of Brasília, Brasília, Brazil.
authors: Hugo
authors: H
authors: de Almeida
authors: LORIA, CNRS UMR 7503, INRIA Grand Est, CAPSID team, University of Lorraine, Vandœuvre-lès-Nancy, France.
authors: Vincent
authors: V
authors: Leroux
authors: Department of Cellular Biology, Laboratory of Host-Pathogen Interface, The University of Brasília, Brasília, Brazil.|Faculty of Ceilândia, The University of Brasília, Brasília, Brazil.
authors: Flávia Nader
authors: FN
authors: Motta
authors: UMR 7245 CNRS, Équipe APE, CP52, Muséum National d'Histoire Naturelle, Paris, France.
authors: Philippe
authors: P
authors: Grellier
authors: LORIA, CNRS UMR 7503, INRIA Grand Est, CAPSID team, University of Lorraine, Vandœuvre-lès-Nancy, France. bernard.maigret@loria.fr.
authors: Bernard
authors: B
authors: Maigret
authors: Department of Cellular Biology, Laboratory of Host-Pathogen Interface, The University of Brasília, Brasília, Brazil.
authors: Jaime M
authors: JM
authors: Santana
authors: Department of Cellular Biology, Laboratory of Host-Pathogen Interface, The University of Brasília, Brasília, Brazil. dourado@unb.br.
authors: Izabela Marques Dourado
authors: IM
authors: Bastos
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D062126:Databases, Chemical; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D000085822:Prolyl Oligopeptidases; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013552:Swine; D013876:Thiophenes / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry; D014344:Trypanocidal Agents / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D001555:Benzene Derivatives; D011743:Pyrimidines; D015842:Serine Proteinase Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; D013876:Thiophenes; D014230:Triazoles; D014344:Trypanocidal Agents; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases
keywords: Binding assays; Catalytic mechanism; Chagas disease; Docking; GOLD; Homology modeling; Molecular dynamics; NAMD; POPTc80; Prolyl oligopeptidase; Structure-based drug design; Trypanosoma cruzi; Virtual screening