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dc.contributor.authorDjikic, Teodora
dc.contributor.authorMarti, Yasmina
dc.contributor.authorSpyrakis, Francesca
dc.contributor.authorLau, Thorsten
dc.contributor.authorBenedetti, Paolo
dc.contributor.authorDavey, Gavin
dc.contributor.authorSchloss, Patrick
dc.contributor.authorYelekçi, Kemal
dc.date.accessioned2019-06-27T08:02:18Z
dc.date.available2019-06-27T08:02:18Z
dc.date.issued2019
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.urihttps://hdl.handle.net/20.500.12469/593
dc.identifier.urihttps://doi.org/10.1080/07391102.2018.1426044
dc.description.abstractParkinson's disease (PD) is characterized by the loss of dopamine-generating neurons in the substantia nigra and corpus striatum. Current treatments alleviate PD symptoms rather than exerting neuroprotective effect on dopaminergic neurons. New drugs targeting the dopaminergic neurons by specific uptake through the human dopamine transporter (hDAT) could represent a viable strategy for establishing selective neuroprotection. Molecules able to increase the bioactive amount of extracellular dopamine thereby enhancing and compensating a loss of dopaminergic neurotransmission and to exert neuroprotective response because of their accumulation in the cytoplasm are required. By means of homology modeling molecular docking and molecular dynamics simulations we have generated 3D structure models of hDAT in complex with substrate and inhibitors. Our results clearly reveal differences in binding affinity of these compounds to the hDAT in the open and closed conformations critical for future drug design. The established in silico approach allowed the identification of promising substrate compounds that were subsequently analyzed for their efficiency in inhibiting hDAT-dependent fluorescent substrate uptake through in vitro live cell imaging experiments. Taken together our work presents the first implementation of a combined in silico/in vitro approach enabling the selection of promising dopaminergic neuron-specific substrates.
dc.language.isoEnglish
dc.publisherTaylor & Francis Inc
dc.subjectDAT
dc.subjectSubstrates
dc.subjectNeuroprotection
dc.subjectVirtual screening
dc.subjectMolecular modeling
dc.titleHuman dopamine transporter: the first implementation of a combined in silico/in vitro approach revealing the substrate and inhibitor specificities
dc.typeArticle
dc.identifier.startpage291
dc.identifier.endpage306
dc.relation.journalJournal of Biomolecular Structure and Dynamics
dc.identifier.issue2
dc.identifier.volume37
dc.identifier.wosWOS:000459906900003
dc.identifier.doi10.1080/07391102.2018.1426044
dc.contributor.khasauthorDjikic, Teodora
dc.contributor.khasauthorYelekçi, Kemal


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