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Citation |
Egyed A, Kiss DJ, Keserű GM. Front. Pharmacol. 2022; 13. |
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Copyright |
(Copyright © 2022, Frontiers Media) |
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DOI |
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PMID |
unavailable |
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Abstract |
G-protein coupled receptors (GPCRs) are considered important therapeutic targets due to their pathophysiological significance and pharmacological relevance. Class A receptors represent the largest group of GPCRs that gives the highest number of validated drug targets. Endogenous ligands bind to the orthosteric binding pocket (OBP) embedded in the intrahelical space of the receptor. During the last 10 years, however, it has been turned out that in many receptors there is secondary binding pocket (SBP) located in the extracellular vestibule that is much less conserved. In some cases, it serves as a stable allosteric site harbouring allosteric ligands that modulate the pharmacology of orthosteric binders. In other cases it is used by bitopic compounds occupying both the OBP and SBP. In these terms, SBP binding moieties might influence the pharmacology of the bitopic ligands. Together with others, our research group showed that SBP binders contribute significantly to the affinity, selectivity, functional activity, functional selectivity and binding kinetics of bitopic ligands. Based on these observations we developed a structure-based protocol for designing bitopic compounds with desired pharmacological profile. Copyright © 2022 Egyed, Kiss and Keserű. Language: en |
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Keywords |
suicide; Review; anxiety; serotonin; pathophysiology; dopamine; histamine; lipophilicity; X ray crystallography; decarboxylation; drug binding site; aripiprazole; muscarinic receptor; fatty acid; cyclic AMP; nerve cell plasticity; G protein coupled receptor; hydroxylation; kinetics; physical chemistry; mitogen activated protein kinase 1; mitogen activated protein kinase 3; allosterism; beta arrestin 2; cariprazine; pharmacology; 3 methylspiperone; adenosine receptor; allosteric; beta arrestin 1; bitopic; cryoelectron microscopy; functional selectivity; GPCR (G-protein coupled receptor); rhodopsin kinase; secondary binding pocket; selectivity |