Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning

Autores
Alberca, Lucas Nicolás; Chuguransky, Sara Rocío; Alvarez, Cora Lilia; Salas Sarduy, Emir; Talevi, Alan
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Malaria is a life-threatening condition that continues being one of global leading causes of death worldwide, being themain cause of death globally in the 5-14 year-old population. The disease is caused by parasites from the Plasmodiumgenre. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first linecombination therapy have led to renewed interest in novel therapeutic options. In this work, our objective was theidentification of novel Falcipan-2 (FP2) inhibitors through the application of an in silico approach and the subsequentin vitro evaluation of the emerging hits. FP2 is a key cysteine protease in the life cycle of P. falciparum constituting apromising target in the search for novel therapies due to their significant hemoglobinase capacity.We have developed a ligand-based model ensemble capable of recognizing FP2 inhibitors from non-inhibitors. Thisensemble has showed a powerful ability for the identification of FP2 inhibitors. The ensemble was applied in a virtualscreening campaign of DrugBank database to identify approved drugs with FP2 inhibitory activity. 4 hits wereacquired and tested against recombinant FP2 using a fluorogenic continuous enzymatic assay under balanced assayconditions ([S]0/KM=1). The reversibility of the interaction, mode of inhibition and Ki were further investigated forvalidated hits. Two drugs, Methacycline and Odanacatib, showed dose-dependent inhibition of FP2. Although bothinhibitors showed reversible interactions with FP2, the compounds displayed different inhibition mechanisms. Doseresponseanalysis at growing substrate concentrations indicated that Odanacatib is a competitive inhibitor of FP2(Ki=98.2 nM), whereas Methacycline displayed non-competitive behaviour (Ki=84.4 μM; α =1.42) being to our bestknowledge the first report of the inhibition of plasmodial cysteine proteases by a tetracycline derivative in a noncompetitivemanner. To access the impact of Methacycline and Odanacatib on the intracellular parasite?sdevelopment, parasite trophozoite forms were treated with the compounds for 48h and the parasitemia was analyzedby light microscopy. Treatment of infected erythrocytes with the compounds caused inhibition in a dose-dependentmanner. These results demonstrate the utility of the in silico approach, since we could find two FP2 inhibitors withantiplasmodial activity with a minimal investment of time and money.
Fil: Alberca, Lucas Nicolás. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Chuguransky, Sara Rocío. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alvarez, Cora Lilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Fil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Conference on drug discovery & development
Dundee
Reino Unido
Centre for Anti-Infectives Research
University of Dundee
Materia
MALARIA
PLASMODIUM FALCIPARUM
FALCIPAIN 2
VIRTUAL SCREENING
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/153829
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/153829
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioningAlberca, Lucas NicolásChuguransky, Sara RocíoAlvarez, Cora LiliaSalas Sarduy, EmirTalevi, AlanMALARIAPLASMODIUM FALCIPARUMFALCIPAIN 2VIRTUAL SCREENINGhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Malaria is a life-threatening condition that continues being one of global leading causes of death worldwide, being themain cause of death globally in the 5-14 year-old population. The disease is caused by parasites from the Plasmodiumgenre. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first linecombination therapy have led to renewed interest in novel therapeutic options. In this work, our objective was theidentification of novel Falcipan-2 (FP2) inhibitors through the application of an in silico approach and the subsequentin vitro evaluation of the emerging hits. FP2 is a key cysteine protease in the life cycle of P. falciparum constituting apromising target in the search for novel therapies due to their significant hemoglobinase capacity.We have developed a ligand-based model ensemble capable of recognizing FP2 inhibitors from non-inhibitors. Thisensemble has showed a powerful ability for the identification of FP2 inhibitors. The ensemble was applied in a virtualscreening campaign of DrugBank database to identify approved drugs with FP2 inhibitory activity. 4 hits wereacquired and tested against recombinant FP2 using a fluorogenic continuous enzymatic assay under balanced assayconditions ([S]0/KM=1). The reversibility of the interaction, mode of inhibition and Ki were further investigated forvalidated hits. Two drugs, Methacycline and Odanacatib, showed dose-dependent inhibition of FP2. Although bothinhibitors showed reversible interactions with FP2, the compounds displayed different inhibition mechanisms. Doseresponseanalysis at growing substrate concentrations indicated that Odanacatib is a competitive inhibitor of FP2(Ki=98.2 nM), whereas Methacycline displayed non-competitive behaviour (Ki=84.4 μM; α =1.42) being to our bestknowledge the first report of the inhibition of plasmodial cysteine proteases by a tetracycline derivative in a noncompetitivemanner. To access the impact of Methacycline and Odanacatib on the intracellular parasite?sdevelopment, parasite trophozoite forms were treated with the compounds for 48h and the parasitemia was analyzedby light microscopy. Treatment of infected erythrocytes with the compounds caused inhibition in a dose-dependentmanner. These results demonstrate the utility of the in silico approach, since we could find two FP2 inhibitors withantiplasmodial activity with a minimal investment of time and money.Fil: Alberca, Lucas Nicolás. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Chuguransky, Sara Rocío. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alvarez, Cora Lilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); ArgentinaFil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaConference on drug discovery & developmentDundeeReino UnidoCentre for Anti-Infectives ResearchUniversity of DundeeUniversity of Dundee2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectConferenciaBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/153829Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning; Conference on drug discovery & development; Dundee; Reino Unido; 2019; 1-1CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://d1ssu070pg2v9i.cloudfront.net/pex/wcair/2019/05/07112934/SOSID-Programme-and-Abstract-book_digital.pdfinfo:eu-repo/semantics/altIdentifier/url/https://wcair.dundee.ac.uk/events/setting-our-sights-on-infectious-diseases/Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:21:19Zoai:ri.conicet.gov.ar:11336/153829instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:21:19.319CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
title Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
spellingShingle Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
Alberca, Lucas Nicolás
MALARIA
PLASMODIUM FALCIPARUM
FALCIPAIN 2
VIRTUAL SCREENING
title_short Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
title_full Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
title_fullStr Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
title_full_unstemmed Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
title_sort Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning
dc.creator.none.fl_str_mv Alberca, Lucas Nicolás
Chuguransky, Sara Rocío
Alvarez, Cora Lilia
Salas Sarduy, Emir
Talevi, Alan
author Alberca, Lucas Nicolás
author_facet Alberca, Lucas Nicolás
Chuguransky, Sara Rocío
Alvarez, Cora Lilia
Salas Sarduy, Emir
Talevi, Alan
author_role author
author2 Chuguransky, Sara Rocío
Alvarez, Cora Lilia
Salas Sarduy, Emir
Talevi, Alan
author2_role author
author
author
author
dc.subject.none.fl_str_mv MALARIA
PLASMODIUM FALCIPARUM
FALCIPAIN 2
VIRTUAL SCREENING
topic MALARIA
PLASMODIUM FALCIPARUM
FALCIPAIN 2
VIRTUAL SCREENING
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Malaria is a life-threatening condition that continues being one of global leading causes of death worldwide, being themain cause of death globally in the 5-14 year-old population. The disease is caused by parasites from the Plasmodiumgenre. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first linecombination therapy have led to renewed interest in novel therapeutic options. In this work, our objective was theidentification of novel Falcipan-2 (FP2) inhibitors through the application of an in silico approach and the subsequentin vitro evaluation of the emerging hits. FP2 is a key cysteine protease in the life cycle of P. falciparum constituting apromising target in the search for novel therapies due to their significant hemoglobinase capacity.We have developed a ligand-based model ensemble capable of recognizing FP2 inhibitors from non-inhibitors. Thisensemble has showed a powerful ability for the identification of FP2 inhibitors. The ensemble was applied in a virtualscreening campaign of DrugBank database to identify approved drugs with FP2 inhibitory activity. 4 hits wereacquired and tested against recombinant FP2 using a fluorogenic continuous enzymatic assay under balanced assayconditions ([S]0/KM=1). The reversibility of the interaction, mode of inhibition and Ki were further investigated forvalidated hits. Two drugs, Methacycline and Odanacatib, showed dose-dependent inhibition of FP2. Although bothinhibitors showed reversible interactions with FP2, the compounds displayed different inhibition mechanisms. Doseresponseanalysis at growing substrate concentrations indicated that Odanacatib is a competitive inhibitor of FP2(Ki=98.2 nM), whereas Methacycline displayed non-competitive behaviour (Ki=84.4 μM; α =1.42) being to our bestknowledge the first report of the inhibition of plasmodial cysteine proteases by a tetracycline derivative in a noncompetitivemanner. To access the impact of Methacycline and Odanacatib on the intracellular parasite?sdevelopment, parasite trophozoite forms were treated with the compounds for 48h and the parasitemia was analyzedby light microscopy. Treatment of infected erythrocytes with the compounds caused inhibition in a dose-dependentmanner. These results demonstrate the utility of the in silico approach, since we could find two FP2 inhibitors withantiplasmodial activity with a minimal investment of time and money.
Fil: Alberca, Lucas Nicolás. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Chuguransky, Sara Rocío. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alvarez, Cora Lilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Fil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Conference on drug discovery & development
Dundee
Reino Unido
Centre for Anti-Infectives Research
University of Dundee
description Malaria is a life-threatening condition that continues being one of global leading causes of death worldwide, being themain cause of death globally in the 5-14 year-old population. The disease is caused by parasites from the Plasmodiumgenre. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first linecombination therapy have led to renewed interest in novel therapeutic options. In this work, our objective was theidentification of novel Falcipan-2 (FP2) inhibitors through the application of an in silico approach and the subsequentin vitro evaluation of the emerging hits. FP2 is a key cysteine protease in the life cycle of P. falciparum constituting apromising target in the search for novel therapies due to their significant hemoglobinase capacity.We have developed a ligand-based model ensemble capable of recognizing FP2 inhibitors from non-inhibitors. Thisensemble has showed a powerful ability for the identification of FP2 inhibitors. The ensemble was applied in a virtualscreening campaign of DrugBank database to identify approved drugs with FP2 inhibitory activity. 4 hits wereacquired and tested against recombinant FP2 using a fluorogenic continuous enzymatic assay under balanced assayconditions ([S]0/KM=1). The reversibility of the interaction, mode of inhibition and Ki were further investigated forvalidated hits. Two drugs, Methacycline and Odanacatib, showed dose-dependent inhibition of FP2. Although bothinhibitors showed reversible interactions with FP2, the compounds displayed different inhibition mechanisms. Doseresponseanalysis at growing substrate concentrations indicated that Odanacatib is a competitive inhibitor of FP2(Ki=98.2 nM), whereas Methacycline displayed non-competitive behaviour (Ki=84.4 μM; α =1.42) being to our bestknowledge the first report of the inhibition of plasmodial cysteine proteases by a tetracycline derivative in a noncompetitivemanner. To access the impact of Methacycline and Odanacatib on the intracellular parasite?sdevelopment, parasite trophozoite forms were treated with the compounds for 48h and the parasitemia was analyzedby light microscopy. Treatment of infected erythrocytes with the compounds caused inhibition in a dose-dependentmanner. These results demonstrate the utility of the in silico approach, since we could find two FP2 inhibitors withantiplasmodial activity with a minimal investment of time and money.
publishDate 2019
dc.date.none.fl_str_mv 2019
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info:eu-repo/semantics/conferenceObject
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status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/153829
Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning; Conference on drug discovery & development; Dundee; Reino Unido; 2019; 1-1
CONICET Digital
CONICET
url http://hdl.handle.net/11336/153829
identifier_str_mv Discovery of novel falcipain 2 inhibitors by in silico guided drug repositioning; Conference on drug discovery & development; Dundee; Reino Unido; 2019; 1-1
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/url/https://wcair.dundee.ac.uk/events/setting-our-sights-on-infectious-diseases/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv University of Dundee
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