The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs.

Attila Egyed,Dóra Judit Kiss,György M. Keserű

doi:10.3389/fphar.2022.847788

Attila Egyed, Dóra Judit Kiss + Show 1 more

Open Access

https://doi.org/10.3389/fphar.2022.847788

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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.

Highlights

G-protein coupled receptors (Figure 1) are among the most popular targets for drug discovery and the development of novel therapeutic and pharmacological tools
One of the major challenges in the field is the identification of subtype and functionally selective compounds with high potency, designed efficacy and appropriate binding kinetics profile, which are essential to avoid side effects
The secondary binding pocket plays a prominent role in achieving selectivity, while orthosteric ligands are mainly responsible for affinity and functional activity

Summary

Introduction

G-protein coupled receptors (Figure 1) are among the most popular targets for drug discovery and the development of novel therapeutic and pharmacological tools. One third of the drugs currently approved by the Food and Drug Administration affects one of the GPCRs (Sriram and Insel, 2018) They are critical in signal transduction of hormones and neurotransmitters, and are pharmacological targets for many diseases (Overington et al, 2006). Studying these receptors may help to elucidate the signaling mechanisms in cells, as they play a crucial role in the regulation of both central and peripherial neurological and physiological processes. Detailed understanding of these processes facilitates the development of more targeted therapies (Christopoulos, 2014). SBPs are found in both the extracellular and intracellular parts of the receptor (Figure 2), some of these binding sites are well separated from the OBP while others may have extended binding pocket-like features such as the 5-HT2A aripirazole structure (PDB: 7VOE) (Chen et al, 2021)

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