112 research outputs found
Development of a Novel Virtual Screening Cascade Protocol to Identify Potential Trypanothione Reductase Inhibitors
The implementation of a novel sequential computational approach that can be used effectively for virtual screening and identification of prospective ligands that bind to trypanothione reductase (TryR) is reported. The multistep strategy combines a ligand-based virtual screening for building an enriched library of small molecules with a docking protocol (AutoDock, X-Score) for screening against the TryR target. Compounds were ranked by an exhaustive conformational consensus scoring approach that employs a rank-by-rank strategy by combining both scoring functions. Analysis of the predicted ligand-protein interactions highlights the role of bulky quaternary amine moieties for binding affinity. The scaffold hopping (SHOP) process derived from this computational approach allowed the identification of several chemotypes, not previously reported as antiprotozoal agents, which includes dibenzothiepine, dibenzooxathiepine, dibenzodithiepine, and polycyclic cationic structures like thiaazatetracyclo-nonadeca-hexaen-3-ium. Assays measuring the inhibiting effect of these compounds on T. cruzi and T. brucei TryR confirm their potential for further rational optimization
Role of Î1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion ofTrypanosoma cruzi
Proline is crucial for energizing critical events throughout the life cycle of Trypanosoma cruzi, the etiological agent of Chagas disease. The proline breakdown pathway consists of two oxidation steps, both of which producereducing equivalents as follows: the conversion of proline to Î1-pyrroline-5-carboxylate (P5C), and the subsequent conversion of P5C to glutamate. We have identified and characterized the Î1-pyrroline-5-carboxylate dehydrogenase from T. cruzi (TcP5CDH) and report here on how this enzyme contributes to a central metabolic pathway in this parasite. Size-exclusionchromatography, two-dimensional gel electrophoresis, and small angle x-ray scattering analysis of TcP5CDH revealed an oligomericstate composed of two subunits of six protomers. TcP5CDH was found to complement a yeast strain deficient in PUT2 activity,confirming the enzyme's functional role; and the biochemical parameters (Km, kcat, and kcat/Km) of the recombinant TcP5CDH were determined, exhibiting values comparable with those from T. cruzi lysates. In addition, TcP5CDH exhibited mitochondrial staining during the main stages of the T. cruzi life cycle. mRNA and enzymatic activity levels indicated the up-regulation (6-fold change) of TcP5CDH during the infectivestages of the parasite. The participation of P5C as an energy source was also demonstrated. Overall, we propose that thisenzymatic step is crucial for the viability of both replicative and infective forms of T. cruzi
In vitro activity of the hydroalcoholic extract of Chenopodium ambrosioides against engorged females of Rhipicephalus (Boophilus) microplus
Potencial cicatricial da Bixa orellana L. em feridas cutĂąneas: estudo em modelo experimental
A miragem do carburante nacional: ĂĄrvores, açĂșcar e o terreno da construção de combustĂveis alternativos no Primeiro Governo Vargas (1930-1945)
Potential utility of hyperbaric oxygen therapy and propolis in enhancing the leishmanicidal activity of glucantime
Trypanocidal, trichomonacidal and cytotoxic components of cultivated Artemisia absinthium Linnaeus (Asteraceae) essential oil
LmABCB3, an atypical mitochondrial ABC transporter essential for Leishmania major virulence, acts in heme and cytosolic iron/sulfur clusters biogenesis
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