| Author | Sinatti, Vanessa de V. C. | |
| Author | Baptista, Luiz Phillippe R. | |
| Author | Ferreira, Marcelo Alves | |
| Author | Dardenne, Laurent | |
| Author | Silva, João Hermínio Martins da | |
| Author | Guimarães, Ana Carolina | |
| Access date | 2018-06-07T15:30:42Z | |
| Available date | 2018-06-07T15:30:42Z | |
| Document date | 2017 | |
| Citation | SINATTI, Vanessa de V. C. et al. In silico identification of inhibitors of ribose 5-phosphate isomerase from Trypanosoma cruzi using ligand and structure based approaches. Journal of Molecular Graphics and Modelling, v. 77, p. 168-180, Aug. 2017. | pt_BR |
| ISSN | 1093-3263 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/26771 | |
| Language | eng | pt_BR |
| Publisher | Elsevier | pt_BR |
| Rights | restricted access | pt_BR |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Triagem virtual | pt_BR |
| Subject in Portuguese | Modelagem Farmacóforo | pt_BR |
| Subject in Portuguese | Ancoragem Molecular | pt_BR |
| Subject in Portuguese | Dinâmica Molecular | pt_BR |
| Title | In silico identification of inhibitors of ribose 5-phosphate isomerase from Trypanosoma cruzi using ligand and structure based approaches | pt_BR |
| Type | Article | pt_BR |
| DOI | 10.1016/j.jmgm.2017.08.007 | |
| Abstract | Chagas disease, caused by the protozoan Trypanosoma cruzi, affects approximately seven million people, mainly in Latin America, and causes about 7000 deaths annually. The available treatments are unsatisfactory and search for more effective drugs against this pathogen is critical. In this context, the ribose 5-phosphate isomerase (Rpi) enzyme is a potential drug target mainly due to its function in the pentose phosphate pathway and its essentiality (previously shown in other trypanosomatids). In this study, we propose novel potential inhibitors for the Rpi of T. cruzi (TcRpi) based on a computer-aided approach, including structure-based and ligand-based pharmacophore modeling. Along with a substructural and similarity search, the selected pharmacophore hypotheses were used to screen the purchasable subset of the ZINC Database, yielding 20,183 candidate compounds. These compounds were submitted to molecular docking studies in the TcRpi and Human Rpi (HsRpi) active sites in order to identify potential selective inhibitors for the T. cruzi enzyme. After the molecular docking and ADME-T (absorption, distribution, metabolism, excretion and toxicity)/PAINS (pan-assay interference compounds) screenings, 211 molecules were selected as potential TcRpi inhibitors. Out of these, three compounds - ZINC36975961, ZINC63480117, and ZINC43763931 - were submitted to molecular dynamics simulations and two of them - ZINC36975961 and ZINC43763931- had good performance and made interactions with important active site residues over all the simulation time. These compounds could be considered potential TcRpi inhibitors candidates and also may be used as leads for developing new TcRpi inhibitors. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Laboratório de Modelagem de Sistemas Biológicos. Instituto Nacional de Ciência e Tecnologia em Inovação em Doenças de Populações Negligenciadas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Laboratório Nacional de Computação Científica. Grupo de Modelagem Molecular de Sistemas Biológicos. Petrópolis, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Fiocruz Ceará. Grupo de Modelagem Computacional. Fortaleza, CE, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformática. Rio de Janeiro, RJ. Brasil. | pt_BR |
| Subject | Ribose 5-phosphate isomerase | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Chagas Disease | pt_BR |
| Subject | Virtual screening | pt_BR |
| Subject | Pharmacophore modelling | pt_BR |
| Subject | Molecular docking | pt_BR |
| Subject | Molecular dynamics | pt_BR |
| Subject | ADMET | pt_BR |
| e-ISSN | 1873-4243 | |
| Embargo date | 2030-12-31 | |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
