Nervous system disorders
In-Target versus Off-Target allosteric modulators of GPCRs

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Allosteric modulators represent a new and possibly safer mechanism of action for G protein coupled receptor (GPCR) drugs, whose effect preserve the temporal and local patterns of physiological activity of the endogenous ligand while binding at a different site. We highlight the different molecular mechanisms that could be responsible for this phenotype, distinguishing between the commonly assumed In-Target and potential Off-Target modulators. In-Target modulators are suitable for new chemical entities, while Off-Target may be more suitable for new drug indications.

Section editors:

David Sibley – National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA

C. Anthony Altar – Psychiatric Genomics, Gaithersburg, USA

Theresa Branchek – Lundbeck Research, Paramus, USA

Introduction

Allosteric modulators represent a new and safer mechanism of action for G protein coupled receptor (GPCR) drugs. These are drugs that do not bind directly to the standard binding site of a therapeutic target, but instead bind to a different site modulating the function of the target [1, 2, 3, 4]. Modulators potentiate or diminish the effect of another drug or the endogenous ligand on the therapeutic target of interest. The key therapeutic strategies differ for In-Target and Off-Target modulators. In-Target modulators bind to the same target at a different site not exploited before, and thus offer new chemical space for new chemical entities. Off-Target modulators bind to a different target altogether that modulates the function of the therapeutic target, such as a GPCR heterodimer or a distant protein, which depend on the biological context representing a systems biology concept. There are many potential targets for Off-Target modulators and are thus best suited for new indications of existing drugs.

Section snippets

GPCR allosteric modulators: ‘To be or not to be?’

Although there are many discrepancies in the definition of allosteric modulators, there is widespread agreement in their expected advantages as drugs [1, 2, 3, 4]. One, the allosteric effect is saturable and this means that an excess of the drug cannot have target related toxicity at excess concentrations. Two, unless additional non-allosteric activities are present in the drug, the drug is active only at tissue sites where the normal physiologic release of the natural ligand occurs, and with

In-Target GPCR allosteric modulators: the standard

When we read about GPCR allosteric modulators, it is assumed that we refer to In-Target modulators. However, it can be difficult to determine whether a modulator is an In-Target or Off-Target allosteric modulator. Given the fact that by definition it would bind at a different site, lack of displacement by the endogenous ligand or a drug is not conclusive. Eventually, In-Target allosteric modulators could be validated by labeling allosteric compounds that are displaced by similar allosteric

In-Target GPCR allosteric modulators: discovery strategies

These compounds normally interact at a novel and previously undetected binding site within the receptor, and thus represent primarily an opportunity for the discovery of new chemical entities. Although it is possible that known drugs interact as well on said site, this is expected to be an exception in which case the compound would likely require further chemical optimization for that new mechanism of action. The strategies for the discovery of these compounds face two major issues; the

In-Target GPCR allosteric modulators: therapeutic strategies

We consider three key therapeutic strategies related to their novel mechanism of action, independent of the therapeutic area; potentiators versus attenuators, undruggable GPCR targets, and druggable GPCR targets.

Off-Target GPCR allosteric modulators: reprofiling strategies

Although almost all programs for discovery of GPCR allosteric modulators are based on searching for In-Target modulators, there are many ways for compounds to modulate the function of a GPCR target without interacting directly with it. We could distinguish physically associated proteins and other Off-Targets without direct physical contact, as shown in Fig. 1.

Off-Target modulators may act on a protein physically associated with the GPCR target that forms the receptor complex [16, 26, 27, 28],

Conclusion

We have considered two strategies to discover GPCR allosteric modulator drug candidates, In-Target and Off-Target modulators (see Table 1). As shown schematically in Fig. 1, In-Target modulators are the most commonly studied modulators that represent novel unexplored binding sites and are thus best suited for new chemical entities (NCEs). Off-Target modulators may interact with a large variety of targets that in turn modulate the function of the GPCR target of interest, and are best suited to

Acknowledgements

We are thankful to Boban Thomas, M.D., for valuable comments and for proposing DPP-IV inhibitors as Off-Target allosteric modulators of the GLP-1 GPCR.

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