scholarly journals Controlling receptor function from the extracellular vestibule of G-protein coupled receptors

2020 ◽  
Vol 56 (91) ◽  
pp. 14167-14170
Author(s):  
Attila Egyed ◽  
Katalin Domány-Kovács ◽  
Bence Koványi ◽  
Ferenc Horti ◽  
Dalma Kurkó ◽  
...  
Keyword(s):  
G Protein ◽  
Functional Activity ◽  
Binding Pocket ◽  
G Protein Coupled Receptors ◽  
D3 Receptor ◽  
Receptor Function ◽  
Receptor Ligands ◽  
Dopamine D2 ◽  
G Protein Coupled

Here we show that the functional activity and signalling of dopamine D2 and D3 receptor ligands can be fine tuned from the extracellular secondary binding pocket (SBP) located far from the signalling interface.

scholarly journals Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1647
Author(s):  
Wojciech Pietruś ◽  
Rafał Kurczab ◽  
Dagmar Stumpfe ◽  
Andrzej J. Bojarski ◽  
Jürgen Bajorath
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Ortho Position ◽  
Receptor Ligands ◽  
Clear Trend ◽  
Highly Active ◽  
Biological Compounds ◽  
Common Strategy ◽  
Negative Effect ◽  
G Protein Coupled

Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we identified in the ChEMBL database and analysed 1554 target-based FSAR sets (non-fluorinated compounds and their fluorinated analogues) comprising 966 unique non-fluorinated and 2457 unique fluorinated compounds active against 33 different aminergic GPCRs. Although a relatively small number of activity cliffs (defined as a pair of structurally similar compounds showing significant differences of activity −ΔpPot > 1.7) was found in FSAR sets, it is clear that appropriately introduced fluorine can increase ligand potency more than 50-fold. The analysis of matched molecular pairs (MMPs) networks indicated that the fluorination of the aromatic ring showed no clear trend towards a positive or negative effect on affinity; however, a favourable site for a positive potency effect of fluorination was the ortho position. Fluorination of aliphatic fragments more often led to a decrease in biological activity. The results may constitute the rules of thumb for fluorination of aminergic receptor ligands and provide insights into the role of fluorine substitutions in medicinal chemistry.

scholarly journals Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

2007 ◽  
Vol 7 ◽  
pp. 1073-1081 ◽  
Author(s):  
Luigi F. Agnati ◽  
Giuseppina Leo ◽  
Susanna Genedani ◽  
Diego Guidolin ◽  
Nicola Andreoli ◽  
...  
Keyword(s):  
Immune System ◽  
G Protein ◽  
Cell Metabolism ◽  
G Protein Coupled Receptors ◽  
Host Cells ◽  
Receptor Function ◽  
Viral Receptor ◽  
Receptor Interactions ◽  
Induced Changes ◽  
G Protein Coupled

It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers), but clusters of receptors (receptor mosaics), altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

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