Artículo
Identification of cisapride as new inhibitor of putrescine uptake in Trypanosoma cruzi by combined ligand- and structure-based virtual screening
Dietrich, Roque Carlos
; Alberca, Lucas Nicolás
; Ruiz, María Daniela
; Palestro, Pablo Hernán
; Carrillo, Carolina
; Talevi, Alan
; Gavernet, Luciana
Fecha de publicación:
10/04/2018
Editorial:
Elsevier France-editions Scientifiques Medicales Elsevier
Revista:
European Journal of Medical Chemistry
ISSN:
0223-5234
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old drugs, benznidazole and nifurtimox, which have restricted efficacy against the chronic phase of the illness. To overcome the lack of efficacy of the traditional drugs (and their considerable toxicity), new molecular targets have been studied as starting points to the discovery of new antichagasic compounds. Among them, polyamine transporter TcPAT12 (also known as TcPOT1.1) represents an interesting macromolecule, since polyamines are essential for Trypanosoma cruzi, the parasite that causes the illness, but it cannot synthesize them de novo. In this investigation we report the results of a combined ligand- and structure-based virtual screening for the discovery of new inhibitors of TcPAT12. Initially we filtered out ZINC and Drugbank databases with similarity and QSAR models and then we submitted the candidates to a validated docking based screening. Four structures were selected and tested in T. cruzi epimastigotes proliferation and two of them, Cisapride and [2-(cyclopentyloxy)phenyl]methanamine showed inhibitory effects. Additionally, we performed transport assays which demonstrated that Cisapride interferes with putrescine uptake in a specific mode.
Palabras clave:
CHAGAS DISEASE
,
CISAPRIDE
,
DOCKING
,
DRUG REPOSITIONING
,
QSAR
,
TCPAT12
,
TCPOT1.1
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(CCT - LA PLATA)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - LA PLATA
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - LA PLATA
Articulos(ICT - MILSTEIN)
Articulos de INST.DE CS. Y TECNOLOGIA "DR. CESAR MILSTEIN"
Articulos de INST.DE CS. Y TECNOLOGIA "DR. CESAR MILSTEIN"
Citación
Dietrich, Roque Carlos; Alberca, Lucas Nicolás; Ruiz, María Daniela; Palestro, Pablo Hernán; Carrillo, Carolina; et al.; Identification of cisapride as new inhibitor of putrescine uptake in Trypanosoma cruzi by combined ligand- and structure-based virtual screening; Elsevier France-editions Scientifiques Medicales Elsevier; European Journal of Medical Chemistry; 149; 10-4-2018; 22-29
Compartir
Altmétricas