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New uses for old drugs: pharmacophore‐based screening for the discovery of P‐glycoprotein inhibitors

2011Journal article Open access
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dc.contributor.authorPalmeira, Andreia
dc.contributor.authorRodrigues, Freddy
dc.contributor.authorSousa, Emília
dc.contributor.authorPinto, Madalena
dc.contributor.authorVasconcelos, M. Helena
dc.contributor.authorFernandes, Miguel X.
dc.date.accessioned2023-02-08T14:52:47Z
dc.date.available2023-02-08T14:52:47Z
dc.date.issued2011
dc.description.abstractP-glycoprotein (P-gp) is one of the best character ized transporters responsible for the multidrug resistance phenotype exhibited by cancer cells. Therefore, there is widespread interest in eluci dating whether existing drugs are candidate P-gp substrates or inhibitors. With this aim, a pharma cophore model was created based on known P-gp inhibitors and it was used to screen a database of existing drugs. The P-gp modulatory activity of the best hits was evaluated by several methods such as the rhodamine-123 accumulation assay using K562Dox cell line, and a P-gp ATPase activ ity assay. The ability of these compounds to enhance the cytotoxicity of doxorubicin was assessed with the sulphorhodamine-B assay. Of the 21 hit compounds selected in silico, 12 were found to significantly increase the intracellular accumulation of Rhodamine-123, a P-gp substrate. In addition, amoxapine and loxapine, two tetracy clic antidepressant drugs, were discovered to be potent non-competitive inhibitors of P-gp, causing a 3.5-fold decrease in the doxorubicin GI50 in K562Dox cell line. The overall results provide important clues for the non-label use of known drugs as inhibitors of P-gp. Potent inhibitors with a dibenzoxazepine scaffold emerged from this study and they will be further investigated in order to develop new P-gp inhibitors.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPalmeira, A., Rodrigues, F., Sousa, E., Pinto, M., Vasconcelos, M. H., & Fernandes, M. X. (2011). New uses for old drugs: pharmacophore‐based screening for the discovery of P‐glycoprotein inhibitors. Chemical biology & drug design, 78(1), 57-72.pt_PT
dc.identifier.doi10.1111/j.1747-0285.2011.01089.xpt_PT
dc.identifier.urihttp://hdl.handle.net/10400.13/5016
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectCancerpt_PT
dc.subjectMultidrug-resistance transporterspt_PT
dc.subjectOxazepinept_PT
dc.subjectP-glycoprotein inhibitorspt_PT
dc.subjectPharmacophorept_PT
dc.subjectVirtual screeningpt_PT
dc.subject.pt_PT
dc.subjectFaculdade de Ciências Exatas e da Engenhariapt_PT
dc.titleNew uses for old drugs: pharmacophore‐based screening for the discovery of P‐glycoprotein inhibitorspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage72pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage57pt_PT
oaire.citation.titleChemical Biology & Drug Designpt_PT
oaire.citation.volume78pt_PT
person.familyNameFernandes
person.givenNameMiguel Xavier
person.identifier.ciencia-idED1D-3C7A-467C
person.identifier.orcid0000-0002-1840-616X
person.identifier.ridA-4373-2013
person.identifier.scopus-author-id35466972500
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3
relation.isAuthorOfPublication.latestForDiscovery8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3

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