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

Autores
Alberca, Lucas Nicolás; Chuguransky, Sara Rocío; Álvarez, Cora L.; Talevi, Alan; Salas Sarduy, Emir
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Malaria is among the leading causes of death worldwide. The emergence of Plasmodium falciparum 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 P. falciparum were also studied.
Laboratorio de Investigación y Desarrollo de Bioactivos
Materia
Ciencias Exactas
Malaria
Plasmodium falciparum
Falcipain-2
Drug repositioning
Virtual screening
Drug rescue
Odanacatib
Methacycline
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/107892
Acceder
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network_acronym_str SEDICI
repository_id_str 1329
network_name_str SEDICI (UNLP)
spelling In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2Alberca, Lucas NicolásChuguransky, Sara RocíoÁlvarez, Cora L.Talevi, AlanSalas Sarduy, EmirCiencias ExactasMalariaPlasmodium falciparumFalcipain-2Drug repositioningVirtual screeningDrug rescueOdanacatibMethacyclineMalaria 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.Laboratorio de Investigación y Desarrollo de Bioactivos2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://sedici.unlp.edu.ar/handle/10915/107892enginfo:eu-repo/semantics/altIdentifier/url/http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6691349&blobtype=pdfinfo:eu-repo/semantics/altIdentifier/issn/2296-2646info:eu-repo/semantics/altIdentifier/pmid/31448257info:eu-repo/semantics/altIdentifier/doi/10.3389/fchem.2019.00534info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International (CC BY 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-09-03T10:56:06Zoai:sedici.unlp.edu.ar:10915/107892Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-09-03 10:56:06.947SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
title In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
spellingShingle In <i>silico</i> Guided Drug Repurposing : Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2
Alberca, Lucas Nicolás
Ciencias Exactas
Malaria
Plasmodium falciparum
Falcipain-2
Drug repositioning
Virtual screening
Drug rescue
Odanacatib
Methacycline
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
dc.creator.none.fl_str_mv Alberca, Lucas Nicolás
Chuguransky, Sara Rocío
Álvarez, Cora L.
Talevi, Alan
Salas Sarduy, Emir
author Alberca, Lucas Nicolás
author_facet Alberca, Lucas Nicolás
Chuguransky, Sara Rocío
Álvarez, Cora L.
Talevi, Alan
Salas Sarduy, Emir
author_role author
author2 Chuguransky, Sara Rocío
Álvarez, Cora L.
Talevi, Alan
Salas Sarduy, Emir
author2_role author
author
author
author
dc.subject.none.fl_str_mv Ciencias Exactas
Malaria
Plasmodium falciparum
Falcipain-2
Drug repositioning
Virtual screening
Drug rescue
Odanacatib
Methacycline
topic Ciencias Exactas
Malaria
Plasmodium falciparum
Falcipain-2
Drug repositioning
Virtual screening
Drug rescue
Odanacatib
Methacycline
dc.description.none.fl_txt_mv 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.
Laboratorio de Investigación y Desarrollo de Bioactivos
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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Articulo
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://sedici.unlp.edu.ar/handle/10915/107892
url http://sedici.unlp.edu.ar/handle/10915/107892
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6691349&blobtype=pdf
info:eu-repo/semantics/altIdentifier/issn/2296-2646
info:eu-repo/semantics/altIdentifier/pmid/31448257
info:eu-repo/semantics/altIdentifier/doi/10.3389/fchem.2019.00534
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
Creative Commons Attribution 4.0 International (CC BY 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
Creative Commons Attribution 4.0 International (CC BY 4.0)
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:SEDICI (UNLP)
instname:Universidad Nacional de La Plata
instacron:UNLP
reponame_str SEDICI (UNLP)
collection SEDICI (UNLP)
instname_str Universidad Nacional de La Plata
instacron_str UNLP
institution UNLP
repository.name.fl_str_mv SEDICI (UNLP) - Universidad Nacional de La Plata
repository.mail.fl_str_mv alira@sedici.unlp.edu.ar
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