Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake

Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a cascade virtual screening campaign combining ligand- and structure-based methods. In order to find novel inhibitors of putrescine upta...

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Autores principales:	Alberca, Lucas Nicolás, Sbaraglini, María Laura, Morales, Juan Francisco, Dietrich, Roque Carlos, Ruiz, María Daniela, Pino Martínez, Agustina María, Miranda, Cristian Gabriel, Fraccaroli, Laura Virginia, Alba Soto, Catalina Dirney, Carrillo, Carolina, Palestro, Pablo Hernán, Talevi, Alan
Formato:	Articulo
Lenguaje:	Inglés
Publicado:	2018
Materias:	Ciencias Exactas Biología Medicina Chagas disease Cinnarizine Drug repositioning Drug repurposing Positive predictive value Putrescine uptake Trypanosoma cruzi Virtual screening
Acceso en línea:	http://sedici.unlp.edu.ar/handle/10915/97602 https://ri.conicet.gov.ar/11336/94582 https://www.frontiersin.org/article/10.3389/fcimb.2018.00173/full
Aporte de:	SEDICI (UNLP) de Universidad Nacional de La Plata

id	I19-R120-10915-97602
record_format	dspace
institution	Universidad Nacional de La Plata
institution_str	I-19
repository_str	R-120
collection	SEDICI (UNLP)
language	Inglés
topic	Ciencias Exactas Biología Medicina Chagas disease Cinnarizine Drug repositioning Drug repurposing Positive predictive value Putrescine uptake Trypanosoma cruzi Virtual screening
spellingShingle	Ciencias Exactas Biología Medicina Chagas disease Cinnarizine Drug repositioning Drug repurposing Positive predictive value Putrescine uptake Trypanosoma cruzi Virtual screening Alberca, Lucas Nicolás Sbaraglini, María Laura Morales, Juan Francisco Dietrich, Roque Carlos Ruiz, María Daniela Pino Martínez, Agustina María Miranda, Cristian Gabriel Fraccaroli, Laura Virginia Alba Soto, Catalina Dirney Carrillo, Carolina Palestro, Pablo Hernán Talevi, Alan Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake
topic_facet	Ciencias Exactas Biología Medicina Chagas disease Cinnarizine Drug repositioning Drug repurposing Positive predictive value Putrescine uptake Trypanosoma cruzi Virtual screening
description	Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a cascade virtual screening campaign combining ligand- and structure-based methods. In order to find novel inhibitors of putrescine uptake in <i>Trypanosoma cruzi</i>, an ensemble of linear ligand-based classifiers obtained by has been applied as initial screening filter, followed by docking into a homology model of the putrescine permease <i>Tc</i>PAT12. 1,000 individual linear classifiers were inferred from a balanced dataset. Subsequently, different schemes were tested to combine the individual classifiers: MIN operator, average ranking, average score, average voting, with MIN operator leading to the best performance. The homology model was based on the arginine/agmatine antiporter (AdiC) from <i>Escherichia coli</i> as template. It showed 64% coverage of the entire query sequence and it was selected based on the normalized Discrete Optimized Protein Energy parameter and the GA341 score. The modeled structure had 96% in the allowed area of Ramachandran's plot, and none of the residues located in non-allowed regions were involved in the active site of the transporter. Positivity Predictive Value surfaces were applied to optimize the score thresholds to be used in the ligand-based virtual screening step: for that purpose Positivity Predictive Value was charted as a function of putative yields of active in the range 0.001-0.010 and the Se/Sp ratio. With a focus on drug repositioning opportunities, DrugBank and Sweetlead databases were subjected to screening. Among 8 hits, cinnarizine, a drug frequently prescribed for motion sickness and balance disorder, was tested against <i>T. cruzi</i> epimastigotes and amastigotes, confirming its trypanocidal effects and its inhibitory effects on putrescine uptake. Furthermore, clofazimine, an antibiotic with already proven trypanocidal effects, also displayed inhibitory effects on putrescine uptake. Two other hits, meclizine and butoconazole, also displayed trypanocidal effects (in the case of meclizine, against both epimastigotes and amastigotes), without inhibiting putrescine uptake.
format	Articulo Articulo
author	Alberca, Lucas Nicolás Sbaraglini, María Laura Morales, Juan Francisco Dietrich, Roque Carlos Ruiz, María Daniela Pino Martínez, Agustina María Miranda, Cristian Gabriel Fraccaroli, Laura Virginia Alba Soto, Catalina Dirney Carrillo, Carolina Palestro, Pablo Hernán Talevi, Alan
author_facet	Alberca, Lucas Nicolás Sbaraglini, María Laura Morales, Juan Francisco Dietrich, Roque Carlos Ruiz, María Daniela Pino Martínez, Agustina María Miranda, Cristian Gabriel Fraccaroli, Laura Virginia Alba Soto, Catalina Dirney Carrillo, Carolina Palestro, Pablo Hernán Talevi, Alan
author_sort	Alberca, Lucas Nicolás
title	Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake
title_short	Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake
title_full	Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake
title_fullStr	Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake
title_full_unstemmed	Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake
title_sort	cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake
publishDate	2018
url	http://sedici.unlp.edu.ar/handle/10915/97602 https://ri.conicet.gov.ar/11336/94582 https://www.frontiersin.org/article/10.3389/fcimb.2018.00173/full
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Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake

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