Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight

Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for on...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Lukas Zell [verfasserIn] Alina Bretl [verfasserIn] Veronika Temml [verfasserIn] Daniela Schuster [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	dopamine receptor subtype selectivity GPCR in silico molecular docking secondary binding pocket

Übergeordnetes Werk:	In: Biomedicines - MDPI AG, 2014, 11(2023), 5, p 1468
Übergeordnetes Werk:	volume:11 ; year:2023 ; number:5, p 1468

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/biomedicines11051468

Katalog-ID:	DOAJ094413355

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allfieldsSound	10.3390/biomedicines11051468 doi (DE-627)DOAJ094413355 (DE-599)DOAJ5084bd56c5f9431aa60bab9c0f433eb3 DE-627 ger DE-627 rakwb eng QH301-705.5 Lukas Zell verfasserin aut Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico/in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D<sub<2</sub<R/D<sub<3</sub<R-selective ligands (micro- to nanomolar binding affinities, D<sub<3</sub<R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D<sub<3</sub<R activity (Ki = 2.3 nM) with 263.7-fold D<sub<2</sub<R/D<sub<3</sub<R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting the selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of the structural motifs responsible for DR subtype selectivity, thus benefitting drug development in D<sub<2</sub<R/D<sub<3</sub<R-associated pathologies such as PD. dopamine receptor subtype selectivity GPCR in silico molecular docking secondary binding pocket Biology (General) Alina Bretl verfasserin aut Veronika Temml verfasserin aut Daniela Schuster verfasserin aut In Biomedicines MDPI AG, 2014 11(2023), 5, p 1468 (DE-627)750370483 (DE-600)2720867-9 22279059 nnns volume:11 year:2023 number:5, p 1468 https://doi.org/10.3390/biomedicines11051468 kostenfrei https://doaj.org/article/5084bd56c5f9431aa60bab9c0f433eb3 kostenfrei https://www.mdpi.com/2227-9059/11/5/1468 kostenfrei https://doaj.org/toc/2227-9059 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 5, p 1468
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authorswithroles_txt_mv	Lukas Zell @@aut@@ Alina Bretl @@aut@@ Veronika Temml @@aut@@ Daniela Schuster @@aut@@
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callnumber-first	Q - Science
author	Lukas Zell
spellingShingle	Lukas Zell misc QH301-705.5 misc dopamine receptor misc subtype selectivity misc GPCR misc in silico misc molecular docking misc secondary binding pocket misc Biology (General) Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight
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topic_title	QH301-705.5 Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight dopamine receptor subtype selectivity GPCR in silico molecular docking secondary binding pocket
topic	misc QH301-705.5 misc dopamine receptor misc subtype selectivity misc GPCR misc in silico misc molecular docking misc secondary binding pocket misc Biology (General)
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title	Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight
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title_sort	dopamine receptor ligand selectivity—an in silico/in vitro insight
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title_auth	Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight
abstract	Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico/in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D<sub<2</sub<R/D<sub<3</sub<R-selective ligands (micro- to nanomolar binding affinities, D<sub<3</sub<R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D<sub<3</sub<R activity (Ki = 2.3 nM) with 263.7-fold D<sub<2</sub<R/D<sub<3</sub<R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting the selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of the structural motifs responsible for DR subtype selectivity, thus benefitting drug development in D<sub<2</sub<R/D<sub<3</sub<R-associated pathologies such as PD.
abstractGer	Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico/in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D<sub<2</sub<R/D<sub<3</sub<R-selective ligands (micro- to nanomolar binding affinities, D<sub<3</sub<R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D<sub<3</sub<R activity (Ki = 2.3 nM) with 263.7-fold D<sub<2</sub<R/D<sub<3</sub<R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting the selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of the structural motifs responsible for DR subtype selectivity, thus benefitting drug development in D<sub<2</sub<R/D<sub<3</sub<R-associated pathologies such as PD.
abstract_unstemmed	Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico/in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D<sub<2</sub<R/D<sub<3</sub<R-selective ligands (micro- to nanomolar binding affinities, D<sub<3</sub<R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D<sub<3</sub<R activity (Ki = 2.3 nM) with 263.7-fold D<sub<2</sub<R/D<sub<3</sub<R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting the selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of the structural motifs responsible for DR subtype selectivity, thus benefitting drug development in D<sub<2</sub<R/D<sub<3</sub<R-associated pathologies such as PD.
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title_short	Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight
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Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight

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