Functional genomics to new drug targets

Key Points

  • Functionalization of the human genome is expected to lead to the discovery of novel drug targets that will yield new therapeutic agents.

  • Gene-family mining and comparative genomics can help to identify potential novel targets using in silico approaches.

  • Differential RNA-expression analysis is the highest throughput method for gene functionalization and has been used in many studies to compare disease versus normal or drug-treated versus untreated cells or animals/patients. The limitation of this approach is that it is only an indirect measurement of the proteins that are the actual drug targets.

  • Proteomics is a direct analysis of the protein content, modifications and interactions. Although its throughput is not as high as that of RNA-expression analysis, it looks directly at the potential drug target and can be used to determine the target for drugs with an unknown mechanism of action.

  • Oligonucleotides are used in gene functionalization as a means of rapidly and specifically inhibiting potential targets to simulate the effects of drugs on the target. Antisense oligonucleotides, ribozymes and, most recently, RNA interference (RNAi) can all be used for such target-validation studies.

  • Genome-wide overexpression or knockdown is now possible through large collections of human cDNAs or RNAi reagents. Through automation and robotics, testing of essentially each individual gene in the genome in cell-based phenotypic or reporter assays is now possible. This will allow the building of databases of gene function to predict disease relevance and specificity as well as the potential for being an effective drug target.

  • The sequencing of a number of genomes has revealed a high degree of conservation of many genes and biological pathways across diverse species. This allows for the use of relatively simple model organisms, such as the fruitfly and zebrafish, as surrogates for humans in determining disease pathways.


The completion of the sequencing of the human genome, and those of other organisms, is expected to lead to many potential new drug targets in various diseases, and it is predicted that novel therapeutic agents will be developed against such targets. The role of functional genomics in modern drug discovery is to prioritize these targets and to translate that knowledge into rational and reliable drug discovery. Here, we describe the field of functional genomics and review approaches that have been applied to drug discovery, including RNA profiling, proteomics, antisense and RNA interference, model organisms and high-throughput, genome-wide overexpression or knockdowns, and outline the future directions that are likely to yield new drug targets from genomics.

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Figure 1: Approaches for target discovery and validation.
Figure 2: Computational mining of the human genome.
Figure 3: Novel drug target discovery by proteomics.
Figure 4: Optical sections of adult Drosophila melanogaster eyes.


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The authors would like to thank F. Steele, N. Nanguneri, Q. Ma, F. Buxton, J. van Oostrum, J. Hall, M. Labow, D. Garza, M. Konsolaki and F. Serluca for their contributions to this review.

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Correspondence to Richard Kramer or Dalia Cohen.

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R.K. and D.C. are employees of Novartis.

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P2X 2

P2X 3




Alzheimer's disease



A receptor for which the ligand has not been identified.


A commonly used method for fractionating proteins, in which proteins are first separated (first dimension) on a poly-acrylamide gel according to isoelectric point, then separated at a 90° angle (second dimension) on the basis of molecular mass.


The binding of one strand of a nucleic acid with another strand through the pairing of complementary bases (A–T and G–C) to form a 'double-helix' structure.

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Kramer, R., Cohen, D. Functional genomics to new drug targets. Nat Rev Drug Discov 3, 965–972 (2004).

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