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dc.contributor.author
Hernández González, Jorge E.
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Salas Sarduy, Emir
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Hernández Ramírez, Luisa F.
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Pascual, María José
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Alvarez, Diego Ezequiel
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Pabón, Adriana
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Leite, Vitor B.P.
dc.contributor.author
Pascutti, Pedro G.
dc.contributor.author
Valiente, Pedro A.
dc.date.available
2020-01-31T19:51:03Z
dc.date.issued
2018-12
dc.identifier.citation
Hernández González, Jorge E.; Salas Sarduy, Emir; Hernández Ramírez, Luisa F.; Pascual, María José; Alvarez, Diego Ezequiel; et al.; Identification of (4-(9H-fluoren-9-yl) piperazin-1-yl) methanone derivatives as falcipain 2 inhibitors active against Plasmodium falciparum cultures; Elsevier Science; Biochimica et Biophysica Acta- General Subjects; 1862; 12; 12-2018; 2911-2923
dc.identifier.issn
0304-4165
dc.identifier.uri
http://hdl.handle.net/11336/96418
dc.description.abstract
Background: Falcipain 2 (FP-2) is the hemoglobin-degrading cysteine protease of Plasmodium falciparum most extensively targeted to develop novel antimalarials. However, no commercial antimalarial drugs based on FP-2 inhibition are available yet due to the low selectivity of most FP-2 inhibitors against the human cysteine proteases. Methods: A structure-based virtual screening (SVBS) using Maybridge HitFinder™ compound database was conducted to identify potential FP-2 inhibitors. In vitro enzymatic and cell-growth inhibition assays were performed for the top-scoring compounds. Docking, molecular dynamics (MD) simulations and free energy calculations were employed to study the interaction of the best hits with FP-2 and other related enzymes. Results and conclusions: Two hits based on 4-(9H-fluoren-9-yl) piperazin-1-yl) methanone scaffold, HTS07940 and HTS08262, were identified as inhibitors of FP-2 (half-maximal inhibitory concentration (IC50) = 64 μM and 14.7 μM, respectively) without a detectable inhibition against the human off-target cathepsin K (hCatK). HTS07940 and HTS08262 inhibited the growth of the multidrug-resistant P. falciparum strain FCR3 in culture (half-maximal inhibitory concentrations (IC50) = 2.91 μM and 34 μM, respectively) and exhibited only moderate cytotoxicity against HeLa cells (Half-maximal cytotoxic concentration (CC50) = 133 μM and 350 μM, respectively). Free energy calculations reproduced the experimental affinities of the hits for FP-2 and explained the selectivity with respect to hCatK. General significance: To the best of our knowledge, HTS07940 stands among the most selective FP-2 inhibitors identified by SBVS reported so far, displaying moderate antiplasmodial activity and low cytotoxicity against human cells. Hence, this compound constitutes a promising lead for the design of more potent and selective FP-2 inhibitors.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier Science
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
BINDING MODE
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FALCIPAIN 2
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INHIBITION ASSAY
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MOLECULAR DYNAMICS
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PLASMODIUM FALCIPARUM
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VIRTUAL SCREENING
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Bioquímica y Biología Molecular
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Identification of (4-(9H-fluoren-9-yl) piperazin-1-yl) methanone derivatives as falcipain 2 inhibitors active against Plasmodium falciparum cultures
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-11-25T17:44:24Z
dc.journal.volume
1862
dc.journal.number
12
dc.journal.pagination
2911-2923
dc.journal.pais
Países Bajos
dc.journal.ciudad
Amsterdam
dc.description.fil
Fil: Hernández González, Jorge E.. Universidad de La Habana; Cuba. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
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Fil: Salas Sarduy, Emir. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
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Fil: Hernández Ramírez, Luisa F.. Universidad de Antioquia; Colombia
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Fil: Pascual, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
dc.description.fil
Fil: Alvarez, Diego Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
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Fil: Pabón, Adriana. Universidad de Antioquia; Colombia
dc.description.fil
Fil: Leite, Vitor B.P.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasil
dc.description.fil
Fil: Pascutti, Pedro G.. Universidade Federal do Rio de Janeiro; Brasil
dc.description.fil
Fil: Valiente, Pedro A.. Universidad de La Habana; Cuba
dc.journal.title
Biochimica et Biophysica Acta- General Subjects
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0304416518303039
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.bbagen.2018.09.015
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