We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening.
- Authors
Motta, Flávia; de Almeida, Hugo; Santana, Jaime; Bastos, Izabela; Leroux, Vincent; Maigret, Bernard; Grellier, Philippe
- 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 at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.
- Subjects
ENZYME inhibitors; TRYPANOSOMA cruzi; DRUG use testing; MOLECULAR dynamics; HOMOLOGY (Biology); CHAGAS' disease
- Publication
Journal of Computer-Aided Molecular Design, 2016, Vol 30, Issue 12, p1165
- ISSN
0920-654X
- Publication type
Article
- DOI
10.1007/s10822-016-9985-1