@conference{
author = "Đikić, Teodora and Martí, Yasmina and Spyrakis, Francesca and Lau, Thorsten and Benedetti, Paolo and Davey, Gavin and Schloss, Patrick and Yelekci, Kemal",
year = "2019",
abstract = "Abnormally folded alpha-synuclein protein, dysfunctional mitochondria, increased oxidative stress and reduced dopamine
neurotransmitter synthesis are a
ll extremely well characterized phenomena in Parkinson’s disease (PD) and are thought to be interconnected. While direct
targeting of these areas has demonstrated neuroprotection in vitro and in vivo, there has been a major lack of success in clinical
trials. A critical component in the failure of these clinical trials is the inability to specifically target drugs to dopamine producing
neurons in the brain.
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 kinetics 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 three 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.",
publisher = "Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu",
journal = "2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.",
title = "In silico reconstruction of human dopamine transporter and design of novel neuroprotective drugs for Parkinson’s disease",
pages = "13-14",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4887"
}
