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 f...

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Bibliographic Details
Published in:Biomedicines 2023-05, Vol.11 (5), p.1468
Main Authors: Zell, Lukas, Bretl, Alina, Temml, Veronika, Schuster, Daniela
Format: Article
Language:English
Subjects:
Amino acids
Antipsychotics
Cardiac glycosides
Cardiotonic agents
Dopamine
Dopamine D2 receptors
Dopamine D3 receptors
dopamine receptor
Drug delivery
Drug development
Drugs
Dyskinesia
GPCR
in silico
Ligands
Mental disorders
molecular docking
Movement disorders
Neurodegenerative diseases
Parkinson's disease
Phenols
Proteins
Psychotropic drugs
Schizophrenia
secondary binding pocket
subtype selectivity
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Summary: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 R/D R-selective ligands (micro- to nanomolar binding affinities, D R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D R activity (Ki = 2.3 nM) with 263.7-fold D R/D 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 R/D R-associated pathologies such as PD.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines11051468