Human dopamine transporter: the first implementation of a combined in silico/in vitro approach revealing the substrate and inhibitor specificities

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.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
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.en_US]
dc.identifier.citation7
dc.identifier.doi10.1080/07391102.2018.1426044en_US
dc.identifier.endpage306
dc.identifier.issn0739-1102en_US
dc.identifier.issn1538-0254en_US
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.issue2
dc.identifier.pmid29334320en_US
dc.identifier.scopus2-s2.0-85041109188en_US
dc.identifier.scopusqualityQ2
dc.identifier.startpage291en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12469/593
dc.identifier.urihttps://doi.org/10.1080/07391102.2018.1426044
dc.identifier.volume37en_US
dc.identifier.wosWOS:000459906900003en_US
dc.identifier.wosqualityN/A
dc.institutionauthorDjikic, Teodoraen_US
dc.institutionauthorYelekçi, Kemalen_US
dc.language.isoenen_US
dc.publisherTaylor & Francis Incen_US
dc.relation.journalJournal of Biomolecular Structure and Dynamicsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectDATen_US
dc.subjectSubstratesen_US
dc.subjectNeuroprotectionen_US
dc.subjectVirtual screeningen_US
dc.subjectMolecular modelingen_US
dc.titleHuman dopamine transporter: the first implementation of a combined in silico/in vitro approach revealing the substrate and inhibitor specificitiesen_US
dc.typeArticleen_US
dspace.entity.typePublication

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