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

Egyed, Attila; Domány-Kovács, Katalin; Koványi, Bence; Horti, Ferenc; Kurkó, Dalma; Kiss, Dániel; Pándy-Szekeres, Gáspár; Greiner, István; Keserü, György M.

doi:10.1039/d0cc05532h

Cited by 13 publications

(24 citation statements)

References 33 publications

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“…The antagonistic behaviour of 59 was also preserved in the β-arrestin signalling pathway; following the previous trends introduction of any SP led to an increase in pIC 50 values here as well. In general, the efficacy data measured at both receptors followed similar trends in both modalities as the receptor affinities ( Egyed et al, 2020 ).…”

Section: Bitopic Ligands To Study Selectivity and Functional Selectiv...mentioning

confidence: 77%

“…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 β 2 R highlighting the important role of ECL2 as discussed in more detail in the binding kinetic section of this review.…”

Section: Ligand Binding Pocket Revealed By Experimental Structuresmentioning

confidence: 99%

“… D 2 R and D 3 R ligands with designed functional profile ( Egyed et al, 2020 ). The binding mode of compound 60 and 63 was extracted from the MD simulations.…”

Section: Bitopic Ligands To Study Selectivity and Functional Selectiv...mentioning

confidence: 99%

“…Discussing the recent advances in the allosteric and bitopic field we pointed out several times the usefulness of MD based methods. These simulations can explore the differences in the interaction patterns of congeneric molecules more sensitively compared to docking that could be important to understand the different functional outcome of these ligands ( Egyed et al, 2020 ) and to design compounds with specific pharmacological profile ( McCorvy et al, 2018 ) and they might reveal cryptic pockets opened by ligands ( Ferruz et al, 2018 ) that might be overlooked in simple docking calculations. Mutation studies combined with extensive molecular dynamics modelling the dissociation of the ligands was utilized to clarify the structural basis of the long duration of action and kinetic selectivity of tiotropium for the M 3 receptor ( Tautermann et al, 2013 ).…”

Section: Design Approaches For Allosteric and Bitopic Compoundsmentioning

confidence: 99%

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

2022

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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.

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Section: Bitopic Ligands To Study Selectivity and Functional Selectiv...mentioning

confidence: 77%

Section: Ligand Binding Pocket Revealed By Experimental Structuresmentioning

confidence: 99%

“… D 2 R and D 3 R ligands with designed functional profile ( Egyed et al, 2020 ). The binding mode of compound 60 and 63 was extracted from the MD simulations.…”

Section: Bitopic Ligands To Study Selectivity and Functional Selectiv...mentioning

confidence: 99%

Section: Design Approaches For Allosteric and Bitopic Compoundsmentioning

confidence: 99%

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

2022

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“… 27 − 30 Recently, the field of bitopic ligands has been expanded to other protein classes including kinases, e.g., mTor 31 and PKCα, 32 and a merged bitopic ligand for the nuclear receptor PPARγ. 33 These chemical biology studies have demonstrated that a dual targeting strategy is associated with several advantages over monovalent targeting strategies, including an increased affinity 30 , 34 or selectivity, 30 , 34 − 36 a bias in signaling pathway activation, 30 , 37 and reduced therapeutic resistance. 31 …”

Section: Introductionmentioning

confidence: 99%

Orthosteric and Allosteric Dual Targeting of the Nuclear Receptor RORγt with a Bitopic Ligand

2021

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The RORγt nuclear receptor (NR) is of critical importance for the differentiation and proliferation of T helper 17 (Th17) cells and their production of the pro-inflammatory cytokine IL-17a. Dysregulation of RORγt has been linked to various autoimmune diseases, and small molecule inhibition of RORγt is therefore an attractive strategy to treat these diseases. RORγt is a unique NR in that it contains both a canonical, orthosteric and a second, allosteric ligand binding site in its ligand binding domain (LBD). Hence, dual targeting of both binding pockets constitutes an attractive alternative molecular entry for pharmacological modulation. Here, we report a chemical biology approach to develop a bitopic ligand for the RORγt NR, enabling concomitant engagement of both binding pockets. Three candidate bitopic ligands, Bit-L15 , Bit-L9 , and Bit-L4 , comprising an orthosteric and allosteric RORγt pharmacophore linked via a polyethylene glycol (PEG) linker, were designed, synthesized, and evaluated to examine the influence of linker length on the RORγt binding mode. Bit-L15 and Bit-L9 show convincing evidence of concomitant engagement of both RORγt binding pockets, while the shorter Bit-L4 does not show this evidence, as was anticipated during the ligand design. As the most potent bitopic RORγt ligand, Bit-L15 , antagonizes RORγt function in a potent manner in both a biochemical and cellular context. Furthermore, Bit-L15 displays an increased selectivity for RORγt over RORα and PPARγ compared to the purely orthosteric and allosteric parent compounds. Combined, these results highlight potential advantages of bitopic NR modulation over monovalent targeting strategies.

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