Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach

Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D<sub<2</sub< (D<sub<2</sub<R) has been shown to be involved in central nervous system diseases. While different D<sub<2</sub<R-targeting drug...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Lukas Zell [verfasserIn] Constanze Lainer [verfasserIn] Jakub Kollár [verfasserIn] Veronika Temml [verfasserIn] Daniela Schuster [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	dopamine receptor GPCR in silico pharmacophore modelling virtual screening in vitro

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 27(2022), 14, p 4435
Übergeordnetes Werk:	volume:27 ; year:2022 ; number:14, p 4435

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules27144435

Katalog-ID:	DOAJ040232824

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allfieldsSound	10.3390/molecules27144435 doi (DE-627)DOAJ040232824 (DE-599)DOAJ1db22ed3e414403ea8b19239e8d1cc1d DE-627 ger DE-627 rakwb eng QD241-441 Lukas Zell verfasserin aut Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D<sub<2</sub< (D<sub<2</sub<R) has been shown to be involved in central nervous system diseases. While different D<sub<2</sub<R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D<sub<2</sub<R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D<sub<2</sub<R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D<sub<2</sub<R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D<sub<2</sub<R. This workflow successfully identified six novel D<sub<2</sub<R ligands exerting micro- to nanomolar (most active compound K<sub<I</sub< = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D<sub<2</sub<R-associated pathologies. dopamine receptor GPCR in silico pharmacophore modelling virtual screening in vitro Organic chemistry Constanze Lainer verfasserin aut Jakub Kollár verfasserin aut Veronika Temml verfasserin aut Daniela Schuster verfasserin aut In Molecules MDPI AG, 2003 27(2022), 14, p 4435 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:14, p 4435 https://doi.org/10.3390/molecules27144435 kostenfrei https://doaj.org/article/1db22ed3e414403ea8b19239e8d1cc1d kostenfrei https://www.mdpi.com/1420-3049/27/14/4435 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 27 2022 14, p 4435
language	English
source	In Molecules 27(2022), 14, p 4435 volume:27 year:2022 number:14, p 4435
sourceStr	In Molecules 27(2022), 14, p 4435 volume:27 year:2022 number:14, p 4435
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topic_facet	dopamine receptor GPCR in silico pharmacophore modelling virtual screening in vitro Organic chemistry
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authorswithroles_txt_mv	Lukas Zell @@aut@@ Constanze Lainer @@aut@@ Jakub Kollár @@aut@@ Veronika Temml @@aut@@ Daniela Schuster @@aut@@
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callnumber-first	Q - Science
author	Lukas Zell
spellingShingle	Lukas Zell misc QD241-441 misc dopamine receptor misc GPCR misc in silico misc pharmacophore modelling misc virtual screening misc in vitro misc Organic chemistry Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach
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topic_title	QD241-441 Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach dopamine receptor GPCR in silico pharmacophore modelling virtual screening in vitro
topic	misc QD241-441 misc dopamine receptor misc GPCR misc in silico misc pharmacophore modelling misc virtual screening misc in vitro misc Organic chemistry
topic_unstemmed	misc QD241-441 misc dopamine receptor misc GPCR misc in silico misc pharmacophore modelling misc virtual screening misc in vitro misc Organic chemistry
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title	Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach
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title_sort	identification of novel dopamine d<sub<2</sub< receptor ligands—a combined in silico/in vitro approach
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title_auth	Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach
abstract	Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D<sub<2</sub< (D<sub<2</sub<R) has been shown to be involved in central nervous system diseases. While different D<sub<2</sub<R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D<sub<2</sub<R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D<sub<2</sub<R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D<sub<2</sub<R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D<sub<2</sub<R. This workflow successfully identified six novel D<sub<2</sub<R ligands exerting micro- to nanomolar (most active compound K<sub<I</sub< = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D<sub<2</sub<R-associated pathologies.
abstractGer	Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D<sub<2</sub< (D<sub<2</sub<R) has been shown to be involved in central nervous system diseases. While different D<sub<2</sub<R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D<sub<2</sub<R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D<sub<2</sub<R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D<sub<2</sub<R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D<sub<2</sub<R. This workflow successfully identified six novel D<sub<2</sub<R ligands exerting micro- to nanomolar (most active compound K<sub<I</sub< = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D<sub<2</sub<R-associated pathologies.
abstract_unstemmed	Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D<sub<2</sub< (D<sub<2</sub<R) has been shown to be involved in central nervous system diseases. While different D<sub<2</sub<R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D<sub<2</sub<R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D<sub<2</sub<R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D<sub<2</sub<R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D<sub<2</sub<R. This workflow successfully identified six novel D<sub<2</sub<R ligands exerting micro- to nanomolar (most active compound K<sub<I</sub< = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D<sub<2</sub<R-associated pathologies.
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title_short	Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach
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Identification of Novel Dopamine D<sub<2</sub< Receptor Ligands—A Combined In Silico/In Vitro Approach

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