TY  - CONF
AU  - Đikić, Teodora
AU  - Martí, Yasmina
AU  - Spyrakis, Francesca
AU  - Lau, Thorsten
AU  - Benedetti, Paolo
AU  - Davey, Gavin
AU  - Schloss, Patrick
AU  - Yelekci, Kemal
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4887
AB  - 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.
PB  - Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu
C3  - 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.
T1  - In silico reconstruction of human dopamine transporter and design of novel neuroprotective drugs for Parkinson’s disease
SP  - 13
EP  - 14
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4887
ER  - 

@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"
}

Đikić, T., Martí, Y., Spyrakis, F., Lau, T., Benedetti, P., Davey, G., Schloss, P.,& Yelekci, K.. (2019). In silico reconstruction of human dopamine transporter and design of novel neuroprotective drugs for Parkinson’s disease. in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.
Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu., 13-14.
https://hdl.handle.net/21.15107/rcub_farfar_4887

Đikić T, Martí Y, Spyrakis F, Lau T, Benedetti P, Davey G, Schloss P, Yelekci K. In silico reconstruction of human dopamine transporter and design of novel neuroprotective drugs for Parkinson’s disease. in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.. 2019;:13-14.
https://hdl.handle.net/21.15107/rcub_farfar_4887 .

Đikić, Teodora, Martí, Yasmina, Spyrakis, Francesca, Lau, Thorsten, Benedetti, Paolo, Davey, Gavin, Schloss, Patrick, Yelekci, Kemal, "In silico reconstruction of human dopamine transporter and design of novel neuroprotective drugs for Parkinson’s disease" in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019. (2019):13-14,
https://hdl.handle.net/21.15107/rcub_farfar_4887 .

TY  - JOUR
AU  - Nikolić, Katarina
AU  - Mavridis, Lazaros
AU  - Đikić, Teodora
AU  - Vučićević, Jelica
AU  - Agbaba, Danica
AU  - Yelekci, Kemal
AU  - Mitchell, John B. O.
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2540
AB  - The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug discovery programs. A probabilistic method, the ParzenRosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D-1-R/D-2-R/5-HT2A-R/H-3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Neuroscience
T1  - Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies
VL  - 10
DO  - 10.3389/fnins.2016.00265
ER  - 

@article{
author = "Nikolić, Katarina and Mavridis, Lazaros and Đikić, Teodora and Vučićević, Jelica and Agbaba, Danica and Yelekci, Kemal and Mitchell, John B. O.",
year = "2016",
abstract = "The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug discovery programs. A probabilistic method, the ParzenRosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D-1-R/D-2-R/5-HT2A-R/H-3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Neuroscience",
title = "Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies",
volume = "10",
doi = "10.3389/fnins.2016.00265"
}

Nikolić, K., Mavridis, L., Đikić, T., Vučićević, J., Agbaba, D., Yelekci, K.,& Mitchell, J. B. O.. (2016). Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies. in Frontiers in Neuroscience
Frontiers Media Sa, Lausanne., 10.
https://doi.org/10.3389/fnins.2016.00265

Nikolić K, Mavridis L, Đikić T, Vučićević J, Agbaba D, Yelekci K, Mitchell JBO. Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies. in Frontiers in Neuroscience. 2016;10.
doi:10.3389/fnins.2016.00265 .

Nikolić, Katarina, Mavridis, Lazaros, Đikić, Teodora, Vučićević, Jelica, Agbaba, Danica, Yelekci, Kemal, Mitchell, John B. O., "Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies" in Frontiers in Neuroscience, 10 (2016),
https://doi.org/10.3389/fnins.2016.00265 . .