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Emerging paradigms in GPCR allostery: implications for drug discovery

Nature Reviews Drug Discovery volume 12, pages 630–644 (2013)Cite this article

Subjects

Key Points

  • This Review discusses the potential advantages of allosteric ligands from a drug discovery perspective, and highlights opportunities that arise from these advantages.

  • Here, we first provide a classification of allosteric ligands.

  • 'Bitopic' ligands that bridge both allosteric and orthosteric binding pockets are discussed, along with the detection and quantification of allosteric ligands and their effects.

  • We then examine the probe-dependent nature of allosteric interactions and the implications of this in signalling systems that have multiple endogenous ligands.

  • The potential impact of the metabolism of orthosteric and allosteric ligands on allosteric drug action is also discussed, in addition to the ability of allosteric ligands to induce biased signalling by orthosteric ligands and the therapeutic relevance of this.

  • Key challenges in the identification and development of allosteric drug-like compounds are presented.

  • We also provide evidence of how GPCR dimerization may contribute to allosteric drug action.

  • Finally, we highlight key information gained from the recently solved GPCR structures and discuss how this can influence future drug discovery and screening for allosteric ligands.

Abstract

Allosteric ligands bind to G protein-coupled receptors (GPCRs; also known as seven-transmembrane receptors) at sites that are distinct from the sites to which endogenous ligands bind. The existence of allosteric ligands has enriched the ways in which the functions of GPCRs can be manipulated for potential therapeutic benefit, yet the complexity of their actions provides both challenges and opportunities for drug screening and development. Converging avenues of research in areas such as biased signalling by allosteric ligands and the mechanisms by which allosteric ligands modulate the effects of diverse endogenous ligands have provided new insights into how interactions between allosteric ligands and GPCRs could be exploited for drug discovery. These new findings have the potential to alter how screening for allosteric drugs is performed and may increase the chances of success in the development of allosteric modulators as clinical lead compounds.

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Figure 1: How allosteric ligands influence orthosteric ligand function.
Figure 2: Probe dependence and biased signalling.
Figure 3: Allosteric modulation of metabolites.
Figure 4: Metabolism of allosteric ligands.
Figure 5: Emerging structural insights into allostery.
Figure 6: Strategies for enhancing the translational outcomes of allosteric modulators.

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Acknowledgements

P.M.S. and A.C. are principal research fellows of the National Health and Medical Research Council (NHMRC) of Australia, and their work is funded by an NHMRC program grant (number 519461).

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Authors and Affiliations

  1. Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Drug Discovery Biology, Monash University, Melbourne, 3052, Victoria, Australia

    Denise Wootten, Arthur Christopoulos & Patrick M. Sexton

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  1. Denise Wootten
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Correspondence to Patrick M. Sexton.

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Competing interests

P.M.S. and A.C. receive funding from Servier and Alchemia in the area of GPCR drug discovery.

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FURTHER INFORMATION

Protein Data Bank

PowerPoint slides

Glossary

Lead compounds

Chemical compounds that have the desired pharmacological properties and structures to be used as starting points for chemical modifications to improve their pharmacological and/or pharmacokinetic profile.

Orthosteric binding sites

Ligand binding sites on a G protein-coupled receptor for the endogenous ligand. These binding sites are also recognized by classical competitive antagonists and inverse agonists.

Inverse agonists

Ligands that bind to a receptor and decrease its basal signalling activity.

Positive allosteric modulators

Allosteric modulators that enhance the affinity and/or responsiveness of the orthosteric ligand.

Negative allosteric modulators

Allosteric modulators that decrease the affinity and/or responsiveness of the orthosteric ligand.

Neutral allosteric ligands

(Previously referred to as silent allosteric modulators). Allosteric ligands that bind to a G protein-coupled receptor but do not alter the affinity or efficacy of the orthosteric ligand.

Allosteric interaction

An interaction between two topographically distinct binding sites on the same receptor complex. These interactions can be between two ligand binding sites or between a ligand binding site and an effector binding site.

Probe dependence

The ability of an allosteric ligand to display different cooperativities with individual orthosteric ligands acting at the same G protein-coupled receptor.

Biased signalling

The ability of a ligand to preferentially stabilize specific G protein-coupled receptor conformations at the exclusion of others, with each conformational state associated with its own repertoire of signalling behaviours.

Allosteric modulators

Ligands that bind to an allosteric site on a receptor and modulate the binding and/or signalling efficacy of orthosteric ligands.

Intrinsic efficacy

The ability of a molecule to induce a physiological or pharmacological response when bound to a receptor.

Allosteric binding site

A ligand binding site on a G protein-coupled receptor that is topographically distinct from the orthosteric site.

Partial agonist

An agonist that produces a signalling response that is lower than the maximum response achievable for the given signalling system. Partial agonists can antagonize the effects of full agonists.

Binding assays

Assays that are used to assess ligand affinities and/or the kinetics of ligand binding.

Cooperativity factor-α

A parameter that is used to describe and quantify the intensity of the effect of allosteric ligand binding on the affinity of the orthosteric ligand (and vice versa).

Allosteric antagonists

Ligands that bind to the allosteric site but do not have efficacy, yet their binding disrupts or inhibits the binding of other allosteric ligands.

Negative cooperativity

The ability of a negative allosteric modulator to decrease the affinity or efficacy of an orthosteric ligand. This is defined by a cooperativity factor-α or modulation factor-β that is between 0 and 1.

Competitive ligands

Two or more ligands that bind to (and therefore compete for) the same ligand binding site. This term is typically used to describe orthosteric ligands.

Rate constants

Values that quantify the rate of association and dissociation for the binding of a ligand or an effector to a receptor.

Functional assays

Assays that are used to assess ligand efficacy in defined signalling response pathways.

EC50 value

The concentration of an agonist that produces 50% of the maximal response to the given agonist for a defined signalling response pathway.

Emax value

The maximal response of an agonist for a defined signalling response pathway.

Ehlert model

An allosteric ternary complex model that is used to estimate affinities of allosteric ligands and to quantify the effect of an allosteric ligand on the binding affinity of an orthosteric ligand.

Black–Leff operational model

A model that is used to describe and quantify the ability of an agonist to activate a cellular stimulus response upon binding to a receptor.

Modulation factor-β

A parameter that is used to describe and quantify the allosteric effect of an allosteric ligand on the efficacy of the orthosteric ligand.

Positive cooperativity

The ability of a positive allosteric modulator to enhance the affinity or efficacy of an orthosteric ligand. This is defined by a cooperativity factor-α or modulation factor-β that is greater than 1.

Allosteric agonists

Ligand that bind to an allosteric site and cause G protein-coupled receptor activation in the absence of an orthosteric ligand.

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Wootten, D., Christopoulos, A. & Sexton, P. Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 12, 630–644 (2013). https://doi.org/10.1038/nrd4052

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