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Review
. 2022 Mar 9:13:847788.
doi: 10.3389/fphar.2022.847788. eCollection 2022.

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

Attila Egyed  1 , Dóra Judit Kiss  1 , György M Keserű  1
Affiliations
Review

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

Attila Egyed et al. Front Pharmacol. .

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.

Keywords: GPCR (G-protein coupled receptor); allosteric; bitopic; functional selectivity; selectivity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Class A GPCRs. The structures of the receptors marked with red dots have already been solved experimentally (Kooistra et al., 2021).
FIGURE 2
FIGURE 2
(A) Schematic representation of the main allosteric sites in Class A GPCRs. The OBP, where the endogenous ligands bind to the receptor, is located between the extracellular allosteric site and the sodium binding site, deep in the crevice of the receptor formed by the transmembrane helixes. Some allosteric sites are clearly separated from OBP, while others can be considered as an expansion of the orthosteric pocket. (B) Visualisation of allosteric binding sites for some important compounds related to the review: mevidalen in the D1R (green, PDB code: 7LJD), AP8 in FFAR1 (cyan, PDB code: 5TZY), ORG27569 in CB1 (red, PDB code:6KQI), MIPS521 in A1R (yellow, PDB code: 7LD3), LY2119620 in M2R (magenta, PDB code:4MQT), Cmpd-15PA in β2AR (dark green, PDB code: 5X7D), AS408 in β2AR (dark blue, PDB code:6OBA), cmpd-6fa in β2AR (orange, PDB code: 8N48). Cholesterol was shown to bind to extrahelical binding sites to different TMs that could not be depicted on the figure to maintain clarity. For details please see the recent review of Jakubík and El-Fakahany (2021) and for a review of the allosteric sites at the receptor–lipid bilayer interface please see Wang et al. (2021) (C) Schematic structure of a bitopic compound. The primary pharmacophore that binds to the OBP is linked through a linker to the secondary pharmacophore binding to the SBP.
FIGURE 3
FIGURE 3
Structures of some important bitopic compounds. (A) The unusual “upside-down” binding mode of cariprazine (green) and aripiprazole (cyan) in the inactive 5-HT2A structure. Risperidone (orange) is shown as a reference to highlight the cryptic pocket opened up by aripiprazole and cariprazine. (B) The aligned LSD (Wacker et al., 2017) and ergotamine (Wacker et al., 2013) 5-HT2B structure highlighting that the introduction of an SP can influence the binding mode of the PP. The figure was reproduced from Supplementary Figure S7 of our paper (Egyed, A et al. Controlling Receptor Function from the Extracellular Vestibule of G-Protein Coupled Receptors. Chem. Commun. 2020, 56 (91), 14167–14170) (Egyed et al., 2020). (C) The binding mode of salbutamol (cyan) and salmeterol (green) (Masureel et al., 2018) in the β2R highlighting the important role of ECL2 as discussed in more detail in the binding kinetic section of this review.
FIGURE 4
FIGURE 4
Chemical structure of selected allosteric modulators.
FIGURE 5
FIGURE 5
Designed bitopic ligands and the reference compounds in the study of Keserű et al. (Egyed et al., 2021).
FIGURE 6
FIGURE 6
D2R and D3R ligands with designed functional profile (Egyed et al., 2020). The binding mode of compound 60 and 63 was extracted from the MD simulations. The simulations revealed that the SP motif influence the position of the PP and that might be linked to the observed different functional profile. The figure representing the binding mode is reproduced from the TOC Figure of our original article Egyed, A et al. Controlling Receptor Function from the Extracellular Vestibule of G-Protein Coupled Receptors. Chem. Commun. 2020, 56 (91), 14167–14170.
FIGURE 7
FIGURE 7
Iperoxo derivatives investigated at the M1 receptor in the study of Holze et al. (2020).
See this image and copyright information in PMC

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