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Identification of potential trypanothione reductase inhibitors among commercially available ß-carboline derivatives using chemical space, lead-like and drug-like filters, pharmacophore models and molecular docking.
Rodríguez-Becerra, Jorge; Cáceres-Jensen, Lizethly; Hernández-Ramos, José; Barrientos, Lorena.
Afiliação
  • Rodríguez-Becerra J; Physical and Analytical Chemistry Laboratory, PACHEM, Departament of Chemistry, Basic Science Faculty, Universidad Metropolitana de Ciencias de la Educación, UMCE, Santiago, Chile. jorge.rodriguez@umce.cl.
  • Cáceres-Jensen L; Physical and Analytical Chemistry Laboratory, PACHEM, Departament of Chemistry, Basic Science Faculty, Universidad Metropolitana de Ciencias de la Educación, UMCE, Santiago, Chile. lyzethly.caceres@umce.cl.
  • Hernández-Ramos J; Physical and Analytical Chemistry Laboratory, PACHEM, Departament of Chemistry, Basic Science Faculty, Universidad Metropolitana de Ciencias de la Educación, UMCE, Santiago, Chile.
  • Barrientos L; Chemistry Faculty, Research Center for Nanotechnology and Advanced Materials, CIEN-UC, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago, Chile.
Mol Divers ; 21(3): 697-711, 2017 08.
Article em En | MEDLINE | ID: mdl-28656524
American trypanosomiasis or Chagas disease caused by the protozoan Trypanosoma cruzi (T. cruzi) is an important endemic trypanosomiasis in Central and South America. This disease was considered to be a priority in the global plan to combat neglected tropical diseases, 2008-2015, which indicates that there is an urgent need to develop more effective drugs. The development of new chemotherapeutic agents against Chagas disease can be related to an important biochemical feature of T. cruzi: its redox defense system. This system is based on trypanothione ([Formula: see text],[Formula: see text]-bis(glutathyonil)spermidine) and trypanothione reductase (TR), which are rather unique to trypanosomes and completely absent in mammalian cells. In this regard, tricyclic compounds have been studied extensively due to their ability to inhibit the T. cruzi TR. However, synthetic derivatives of natural products, such as [Formula: see text]-carboline derivatives ([Formula: see text]-CDs), as potential TR inhibitors, has received little attention. This study presents an analysis of the structural and physicochemical properties of commercially available [Formula: see text]-CDs in relation to compounds tested against T. cruzi in previously reported enzymatic assays and shows that [Formula: see text]-CDs cover chemical space that has not been considered for the design of TR inhibitors. Moreover, this study presents a ligand-based approach to discover potential TR inhibitors among commercially available [Formula: see text]-CDs, which could lead to the generation of promising [Formula: see text]-CD candidates.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tripanossomicidas / Trypanosoma cruzi / Carbolinas / Inibidores Enzimáticos / NADH NADPH Oxirredutases Tipo de estudo: Diagnostic_studies Idioma: En Revista: Mol Divers Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Chile País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tripanossomicidas / Trypanosoma cruzi / Carbolinas / Inibidores Enzimáticos / NADH NADPH Oxirredutases Tipo de estudo: Diagnostic_studies Idioma: En Revista: Mol Divers Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Chile País de publicação: Holanda