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Target deconvolution strategies in drug discovery

Key Points

  • In this postgenomic era, the perceived 'failure' of target-based drug discovery (in part owing to the complexities of biological systems and disease pathophysiology) has recently led to the renaissance of a more holistic approach that involves screening small organic molecules to determine whether they elicit any phenotypic changes in mammalian cells and model organisms.

  • The retrospective identification of the molecular targets that underlie observed phenotypic responses — termed target deconvolution — is important for elucidating biological mechanisms of disease and will also greatly aid rational drug design and enable efficient structure–activity relationship studies to be carried out in a chemical optimization programme by configuration of target-specific assays.

  • A wide range of experimental strategies can in principle be applied to the identification of targets that mediate phenotypic effects. The choice will often mainly be influenced by the properties of the small molecule.

  • Methods that lead to the direct identification of targets typically exploit the affinity between the small organic molecule and its target protein. These methods include affinity chromatography, three-hybrid systems, phage and mRNA display, protein and 'reverse-transfected' cell microarrays, and biochemical suppression.

  • Methods that are based on comprehensive DNA microarray or proteomics analyses can aid target deconvolution because they investigate the mode of action of an active small molecule. In a more indirect way, these technologies can also lead to the identification of molecular targets.

  • The final aim of target deconvolution is not only the identification of biological targets that directly interact with the small molecule, but also the demonstration that the target's modulation is associated with functional effects that are detectable in the phenotypic assay. The 'authenticity' of targets can be confirmed by functional studies that employ a variety of methods, such as RNA interference and protein overexpression.

  • Since phenotype-based drug discovery regained momentum, target deconvolution has become an important aspect of current drug discovery.


Recognition of some of the limitations of target-based drug discovery has recently led to the renaissance of a more holistic approach in which complex biological systems are investigated for phenotypic changes upon exposure to small molecules. The subsequent identification of the molecular targets that underlie an observed phenotypic response — termed target deconvolution — is an important aspect of current drug discovery, as knowledge of the molecular targets will greatly aid drug development. Here, the broad panel of experimental strategies that can be applied to target deconvolution is critically reviewed.

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Figure 1: Phenotype-based versus target-based drug discovery.
Figure 2: Affinity-chromatography-based methods for target deconvolution.
Figure 3: Three-hybrid systems for target deconvolution.
Figure 4: Display technologies for target deconvolution.
Figure 5: Microarray technologies for target deconvolution.
Figure 6: Biochemical suppression in target deconvolution.


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Correspondence to Georg C. Terstappen.

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Rational drug design

A strategy by which drug molecules are developed based on knowledge of the target protein, in particular its three-dimensional structure and/or the ligands that bind to it.

Structure–activity relationship studies

Studies in which the chemical structure of a bioactive small molecule is modified (for example, by insertion of new chemical groups) to investigate the effect of this modification on the molecule's biological activity. The aim of such studies in a chemical optimization programme is typically to improve the characteristics of the compound, such as its potency and selectivity.


FK506 (also known as Tacrolimus or Fujimycin) is an immunosuppressant organic molecule that binds to the immunophilin FKBP12 (FK506 binding protein 12 kDa), which functions as a protein-folding chaperone for proteins that contain proline residues. Owing to the high affinity between FK506 and FKBP12 (with a dissociation constant of 1.6 nM) and the high cellular abundance of the latter, this pair is often used as a model system for proof-of-concept experiments of affinity-based technologies.

Dissociation constant

(kD). A measure of the affinity of a ligand (for example, a small molecule) for a protein. Its numerical value depends on the equilibrium between the undissociated and the dissociated forms of the molecular complex. The smaller the dissociation constant, the tighter the ligand is bound (or the higher its affinity for the target protein).


The derivatization of molecules with the small organic molecule biotin (also known as vitamin H or vitamin B7). Biotinylation enables molecules to bind to streptavidin with high affinity (with a dissociation constant of 10−15 M) — a property that has widespread applications in biotechnology.

cDNA library

A library comprised of cDNAs that are obtained when mRNA is extracted from a cell and reverse transcribed. The library thus represents all transcribed sequences and hence all proteins that the cell was expressing.

Sequence-similarity search

A type of search that provides information about how one nucleotide or protein sequence is related to another. The similarity between the two sequences is expressed as a percentage of sequence identity, and can be used to identify a target protein. Typically, pairwise sequence-search methods such as BLAST and FASTA are used.

Reporter gene assay

An assay that is used to investigate the modulation of a signal transduction pathway. An easily detectable reporter gene, such as luciferase, is fused to the promoter sequence of downstream target genes of the pathway under study; modulation of the pathway, such as activation or inhibition, will lead to changes in reporter gene expression (in the case of luciferase, these changes will be measured as luminescence).

Matrix-assisted laser desorption/ionization mass spectrometry

(MALDI-MS). An analytical technique that is often used to identify biomolecules such as proteins after they have (typically) been isolated by gel electrophoresis.

DNA microarray analysis

A technique that uses DNA microarrays (gene chips) to investigate the expression of thousands of genes or of a complete genome in parallel. DNA molecules are immobilized on a solid support, then labelled nucleotides are hybridized to their complementary sequences and their signals are detected.

Haploinsufficiency profiling

A chemical genomics assay that uses a heterozygous yeast deletion strain in which the gene dosage is reduced to one copy, resulting in a strain that is sensitized to compounds that inhibit the product of the heterozygous locus.

Surface plasmon resonance

An optical biosensor technology that measures the association (kA) and dissociation (kD) constants of interactions in a label-free manner. The small-molecule ligand is immobilized onto the surface of a sensor chip and any interaction with the putative target protein will lead to an increase in the refractive index, which is measured in real time.

Resonance acoustic profiling

A technology that characterizes molecular binding interactions through the use of oscillating acoustic resonators. Any interaction between a small molecule and its target protein is directly detected by resonating quartz crystals.

RNA interference

A method for silencing gene expression. A small double-stranded RNA is introduced into the cell to inhibit the expression of the corresponding mRNA, thus preventing translation of the gene into protein.

Polypharmacologic compounds

Compounds that bind to multiple cellular targets to mediate their clinical effects.

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Terstappen, G., Schlüpen, C., Raggiaschi, R. et al. Target deconvolution strategies in drug discovery. Nat Rev Drug Discov 6, 891–903 (2007).

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