Zell, L.; Bretl, A.; Temml, V.; Schuster, D. Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight. Biomedicines2023, 11, 1468.
Zell, L.; Bretl, A.; Temml, V.; Schuster, D. Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight. Biomedicines 2023, 11, 1468.
Zell, L.; Bretl, A.; Temml, V.; Schuster, D. Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight. Biomedicines2023, 11, 1468.
Zell, L.; Bretl, A.; Temml, V.; Schuster, D. Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight. Biomedicines 2023, 11, 1468.
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 FDA, only a very small number is 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 D2R/D3R-selective ligands (micro- to nanomolar binding affinities, D3R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D3R activity (KI = 2.3 nM) with 263.7-fold D2R/D3R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of structural motifs responsible for DR subtype selectivity, thus, benefitting drug development in D2R/D3R-associated pathologies like PD.
Keywords
dopamine receptor; subtype selectivity; GPCR; in silico; molecular docking; secondary binding pocket; in vitro; HTRF
Subject
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
