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dc.contributor.author
Gantner, Melisa Edith
dc.contributor.author
Peroni, Roxana Noemi
dc.contributor.author
Morales, Juan Francisco
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Villalba, Maria Luisa
dc.contributor.author
Ruiz, María Esperanza
dc.contributor.author
Talevi, Alan
dc.date.available
2018-12-05T19:13:34Z
dc.date.issued
2017-08
dc.identifier.citation
Gantner, Melisa Edith; Peroni, Roxana Noemi; Morales, Juan Francisco; Villalba, Maria Luisa; Ruiz, María Esperanza; et al.; Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage; American Chemical Society; Journal of Chemical Information and Modeling; 57; 8; 8-2017; 1868-1880
dc.identifier.issn
1549-9596
dc.identifier.uri
http://hdl.handle.net/11336/65912
dc.description.abstract
Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion. The best model ensemble consists in averaging the ranking of the 12 decision trees that showed the best performance on the training set, which also demonstrated a good performance for the test set. It was experimentally validated using the ex vivo everted rat intestinal sac model. Five anticonvulsant drugs classified as nonsubstrates for BRCP by the model ensemble were experimentally evaluated, and none of them proved to be a BCRP substrate under the experimental conditions used, thus confirming the predictive ability of the model ensemble. The model ensemble reported here is a potentially valuable tool to be used as an in silico ADME filter in computer-aided drug discovery campaigns intended to overcome BCRP-mediated multidrug resistance issues and to prevent drug-drug interactions.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Atp Binding Cassette Transporter
dc.subject
Drug Resistance, Multiple/Drug Effects
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Drug Design
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Computational Biology/Methods
dc.subject.classification
Otras Ciencias Químicas
dc.subject.classification
Ciencias Químicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.title
Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-10-23T19:45:32Z
dc.journal.volume
57
dc.journal.number
8
dc.journal.pagination
1868-1880
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Washington
dc.description.fil
Fil: Gantner, Melisa Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina
dc.description.fil
Fil: Peroni, Roxana Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
dc.description.fil
Fil: Morales, Juan Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina
dc.description.fil
Fil: Villalba, Maria Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina
dc.description.fil
Fil: Ruiz, María Esperanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina
dc.description.fil
Fil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; Argentina
dc.journal.title
Journal of Chemical Information and Modeling
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/acs.jcim.7b00016
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1021/acs.jcim.7b00016
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