Drug Target Identification

Drug target identification is the first stage of rational discovery: choosing the biological molecule — most often a protein such as a receptor, enzyme, or ion channel — whose modulation is expected to produce a therapeutic effect. It pairs naturally with target validation, which gathers evidence that engaging the chosen target actually alters the disease. Because every later step builds on this choice, a poorly chosen or weakly validated target is a leading cause of downstream failure.

Definition

Drug target identification is the process of selecting the biological entity, usually a protein, whose modulation is hypothesised to be therapeutically beneficial; target validation is the accumulation of evidence that modulating that entity affects the disease as intended.

Scope

This topic covers what makes a molecule a credible drug target, the concept of druggability and the druggable genome, the distinction between identifying and validating a target, and the sources of evidence (genetic, biochemical, pharmacological) used to support a target. It is a reference treatment and does not give clinical or prescribing guidance.

Core questions

• What makes a biological molecule a plausible and druggable target?
• How is a target's link to disease established and validated?
• How many distinct molecular targets do existing drugs actually act on?
• What evidence (genetic, chemical, phenotypic) best supports a target before investment in screening?

Key concepts

• Druggability
• Druggable genome
• Target validation
• Receptors, enzymes, ion channels and transporters as targets
• Genetic and chemical validation
• On-target versus off-target effects

Key theories

The druggable genome

Only a subset of human gene products have binding sites able to bind drug-like small molecules with useful affinity; estimating this 'druggable' subset, and its overlap with disease-modifying genes, frames which targets are realistically pursuable.

Mechanisms

Targets are nominated from many sources: disease biology, genetic associations, expression patterns, and observed pharmacology. A candidate target is assessed for druggability — whether it possesses a binding pocket capable of accommodating a drug-like molecule — and for its causal link to the disease. Validation marshals converging evidence: genetic perturbation (knockout, knockdown), pharmacological modulation with tool compounds, and demonstration that engaging the target changes a disease-relevant readout. Analyses of the molecular targets of approved drugs show that the marketed pharmacopoeia acts on a relatively small number of distinct targets, which both motivates the search for new druggable targets and tempers expectations of how many exist.

Clinical relevance

Target choice ultimately determines a drug's intended mechanism and much of its selectivity and side-effect profile, so understanding target identification helps explain why classes of medicines behave as they do. This entry is educational and describes how targets are selected; it is not guidance for diagnosis or treatment.

Evidence & guidelines

Evidence here is methodological and analytical rather than from clinical trials. Key reference points are estimates of the druggable genome and counts of the distinct molecular targets of approved drugs, together with retrospective analyses of how validated targets contributed to successful medicines.

History

Before molecular biology made specific proteins accessible, drugs were often discovered without a defined target. The sequencing of the human genome prompted formal estimates of how many gene products could be drugged, and Hopkins and Groom's 2002 concept of the druggable genome gave the field a vocabulary for prioritising targets. Subsequent target counts of marketed drugs refined understanding of how much of that potential had been realised.

Debates

How is target validation best achieved?

Genetic, chemical, and phenotypic evidence each have limitations, and a target validated by one method may fail when modulated by a drug; the strength and combination of validation evidence needed before committing resources remains a practical judgement.

Key figures

• Andrew Hopkins
• Colin Groom
• John Overington

Seminal works

• hopkins-groom-2002
• overington-2006

Frequently asked questions

What is the difference between target identification and target validation?

Identification is choosing the biological molecule to act on; validation is gathering evidence that modulating that molecule actually changes the disease as hoped.

What does it mean for a target to be 'druggable'?

A druggable target has a binding site capable of binding a drug-like molecule with sufficient affinity to produce a useful effect; not all disease-relevant proteins are druggable in this sense.