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

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Date
2019
Author
Djikic, Teodora
Marti, Yasmina
Spyrakis, Francesca
Lau, Thorsten
Benedetti, Paolo
Davey, Gavin
Schloss, Patrick
Yelekçi, Kemal
Abstract
Parkinson'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.

Source

Journal of Biomolecular Structure and Dynamics

Issue

2

Volume

37

Pages

291-306

URI

https://hdl.handle.net/20.500.12469/593
https://doi.org/10.1080/07391102.2018.1426044

Collections

  • Araştırma Çıktıları / PubMed [194]
  • Araştırma Çıktıları / Scopus [1565]
  • Araştırma Çıktıları / WOS [1518]
  • Biyoinformatik ve Genetik / Bioinformatics and Genetics [220]

Keywords

DAT
Substrates
Neuroprotection
Virtual screening
Molecular modeling

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