| Title: |
Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening |
| Authors: |
de Almeida, Hugo; Leroux, Vincent; Motta, Flávia Nader; Grellier, Philippe; Maigret, Bernard; Santana, Jaime Martins; Bastos, Izabela Marques Dourado |
| Contributors: |
Universidade de Brasilia = University of Brasilia Brasília (UnB); Computational Algorithms for Protein Structures and Interactions (CAPSID); Centre Inria de l'Université de Lorraine; Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS); Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA); Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA); Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS); Molécules de Communication et Adaptation des Micro-Organismes (MCAM); Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Brésil (CNPq) |
| Source: |
ISSN: 0920-654X. |
| Publisher Information: |
CCSD; Springer Verlag |
| Publication Year: |
2016 |
| Subject Terms: |
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1007/s10822-016-9985-1 |
| Availability: |
https://inria.hal.science/hal-01392842; https://doi.org/10.1007/s10822-016-9985-1 |
| Accession Number: |
edsbas.78C7E5CF |
| Database: |
BASE |