In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

Malaria is among the leading causes of death worldwide. The emergence of <i>Plasmodium falciparum</i> resistant strains with reduced sensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector management have led to renewed interes...

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Detalles Bibliográficos
Autores principales:	Alberca, Lucas Nicolás, Chuguransky, Sara Rocío, Álvarez, Cora L., Talevi, Alan, Salas Sarduy, Emir
Formato:	Articulo
Lenguaje:	Inglés
Publicado:	2019
Materias:	Ciencias Exactas Malaria Plasmodium falciparum Falcipain-2 Drug repositioning Virtual screening Drug rescue Odanacatib Methacycline
Acceso en línea:	http://sedici.unlp.edu.ar/handle/10915/107892 http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6691349&blobtype=pdf
Aporte de:	SEDICI (UNLP) de Universidad Nacional de La Plata

id	I19-R120-10915-107892
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 Malaria Plasmodium falciparum Falcipain-2 Drug repositioning Virtual screening Drug rescue Odanacatib Methacycline
spellingShingle	Ciencias Exactas Malaria Plasmodium falciparum Falcipain-2 Drug repositioning Virtual screening Drug rescue Odanacatib Methacycline Alberca, Lucas Nicolás Chuguransky, Sara Rocío Álvarez, Cora L. Talevi, Alan Salas Sarduy, Emir In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
topic_facet	Ciencias Exactas Malaria Plasmodium falciparum Falcipain-2 Drug repositioning Virtual screening Drug rescue Odanacatib Methacycline
description	Malaria is among the leading causes of death worldwide. The emergence of <i>Plasmodium falciparum</i> resistant strains with reduced sensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector management have led to renewed interest in novel therapeutic options. Here, we report the development and validation of an ensemble of ligand-based computational models capable of identifying falcipain-2 inhibitors, and their subsequent application in the virtual screening of DrugBank and Sweetlead libraries. Among four hits submitted to enzymatic assays, two (odanacatib, an abandoned investigational treatment for osteoporosis and bone metastasis, and the antibiotic methacycline) confirmed inhibitory effects on falcipain-2, with Ki of 98.2 nM and 84.4µM. Interestingly, Methacycline proved to be a non-competitive inhibitor (α = 1.42) of falcipain-2. The effects of both hits on falcipain-2 hemoglobinase activity and on the development of <i>P. falciparum</i> were also studied.
format	Articulo Articulo
author	Alberca, Lucas Nicolás Chuguransky, Sara Rocío Álvarez, Cora L. Talevi, Alan Salas Sarduy, Emir
author_facet	Alberca, Lucas Nicolás Chuguransky, Sara Rocío Álvarez, Cora L. Talevi, Alan Salas Sarduy, Emir
author_sort	Alberca, Lucas Nicolás
title	In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
title_short	In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
title_full	In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
title_fullStr	In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
title_full_unstemmed	In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
title_sort	in <i>silico</i> guided drug repurposing : discovery of new competitive and non-competitive inhibitors of falcipain-2
publishDate	2019
url	http://sedici.unlp.edu.ar/handle/10915/107892 http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6691349&blobtype=pdf
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bdutipo_str	Repositorios
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In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2

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