Off-Target Effects and Polypharmacology

Few drugs bind only their intended target. Off-target effects are the pharmacological consequences of a drug interacting with other proteins, and they can be liabilities — sources of toxicity — or, when harnessed deliberately, assets. Polypharmacology is the study and intentional design of molecules that act on several targets at once, reframing drug action from isolated lock-and-key pairs to a connected network of interactions.

Definition

Off-target effects are the actions of a drug that result from binding molecular targets other than the intended one; polypharmacology is the property — or design strategy — whereby a single drug deliberately or incidentally acts on multiple targets to produce its overall effect.

Scope

This topic covers the origins of off-target binding, how it is mapped and predicted, the distinction between liability and opportunity, and the deliberate strategy of polypharmacology, including network pharmacology and drug repositioning. It is a reference and educational entry and gives no prescribing or treatment advice.

Core questions

• Why do most drugs bind more than one target?
• How are off-target interactions detected, mapped, and predicted?
• When does off-target activity become a safety liability and when an opportunity?
• What is network pharmacology, and how does it differ from the one-drug-one-target model?
• How does off-target activity enable drug repositioning?

Key concepts

• Off-target binding
• Target promiscuity
• Pharmacological space
• Network pharmacology
• Multi-target (multi-ligand) drugs
• Side-effect target prediction
• Drug repositioning / repurposing

Mechanisms

Off-target binding occurs because binding sites on unrelated proteins can share enough shape and chemistry to accommodate the same molecule, so a drug's activity is distributed across a region of 'pharmacological space' rather than confined to one target (Paolini et al., 2006). Computational and chemical-biology methods can predict which secondary targets a drug is likely to hit, and large-scale testing has confirmed that predicted off-target interactions frequently correspond to observed side effects (Lounkine et al., 2012). The network-pharmacology view treats drugs and targets as an interconnected system in which a perturbation propagates through the network, which both explains off-target toxicity and motivates the intentional design of multi-target agents (Hopkins, 2008). The same promiscuity underlies drug repositioning, where an existing drug's secondary activity is developed into a new indication (Ashburn & Thor, 2004).

Clinical relevance

Off-target activity is part of how a drug's unexpected effects — both adverse and beneficial — are understood, and the polypharmacology and repositioning concepts inform how the wider pharmacological literature reasons about drug action. This entry is descriptive and is not a basis for individual diagnostic or treatment decisions.

Evidence & guidelines

The scale of drug-target interactions has been quantified by target-count surveys (Overington et al., 2006) and by chemogenomic mapping of pharmacological space (Paolini et al., 2006), while systematic prediction-and-testing studies (Lounkine et al., 2012) provide experimental evidence that off-target predictions track real side effects. These are descriptive research syntheses and primary studies rather than clinical practice guidelines.

History

The one-drug-one-target ideal dominated twentieth-century drug discovery, but accumulating evidence of promiscuous binding, together with the genomic-era ability to profile a compound against many targets, shifted the picture. The mapping of 'pharmacological space' (Paolini et al., 2006) and the formulation of network pharmacology (Hopkins, 2008) recast off-target activity from an aberration into an intrinsic feature of drug action, and the recognition that secondary activities could be developed into new indications established drug repositioning (Ashburn & Thor, 2004) as a distinct strategy.

Debates

Is polypharmacology a problem to be minimised or a strategy to be exploited?

Off-target activity is a major source of toxicity, arguing for cleaner, more selective drugs; yet for complex diseases acting on several targets can outperform a single-target agent, so whether to suppress or design for multi-target action depends on the therapeutic context.

Key figures

• Andrew L. Hopkins
• Brian K. Shoichet
• John P. Overington

Seminal works

• hopkins-2008-poly
• paolini-2006-poly
• lounkine-2012
• ashburn-thor-2004

Frequently asked questions

Is an off-target effect the same as a side effect?

They overlap but are not identical: an off-target effect is defined by its molecular cause (binding a protein other than the intended target), whereas a side effect is any unwanted clinical effect, which may stem either from off-target binding or from the on-target action itself.

How can the same molecule treating one disease be repurposed for another?

Because most drugs bind several targets, a secondary interaction that is irrelevant or unwanted in the original indication may be therapeutically useful for a different condition, which is the basis of drug repositioning.