Elsevier

Drug Discovery Today

Volume 6, Issue 6, 15 March 2001, Pages 316-323
Drug Discovery Today

Review
Impact of human genome sequencing for in silico target discovery

https://doi.org/10.1016/S1359-6446(01)01724-XGet rights and content

Abstract

The year 2000 stands as a landmark in modern biology: the first draft of the human genome sequence has been completed. For the pharmaceutical industry, this achievement provides tremendous opportunities because the genomic sequence exposes all human drug targets for therapeutic intervention. The challenge for the pharmaceutical companies is to exploit this definitive resource for the identification of potential molecular targets, rapid characterization of their function and validation of their involvement in disease pathology. Bioinformatics approaches provide increasingly crucial tools to systematically support this exploratory target drug discovery activity.

Section snippets

Nature of the human genomic sequence

In 1995, an international public consortium outlined the plan to complete the human genome sequence. The agreed strategy was to use genomic clones from a physical map and to subject the chosen clones to shotgun sequencing. Several rounds of sequencing are necessary to achieve the target of 99.99% accuracy and ten times coverage for the high quality or finished sequence. Because of the progress in sequencing technology and in response to the pressure from private sequencing initiatives, the

How many opportunities?

The human genome sequence contains sufficient information to identify novel opportunities or genes for therapeutic intervention. Until recently, the main source of novelty came from expressed sequence tags (ESTs) 7, 8. EST collections have proven to be useful for identifying novel targets, for example, cathepsin K 9. However, rare transcripts or genes with a limited pattern of expression, although attractive as drug targets, are the most difficult to identify using EST technology. Because of

Discovery genomics: a strategy to identify in silico novel targets

Perhaps the simplest strategy to identify potential drug targets from the human genome is to use bioinformatics tools and the numerous sequence databases available, in a process known as ‘discovery genomics’ 30 (Fig. 1). Gene predictions from ab initio or sequence similarity programs can be used against databases of known effective drug target classes, such as GPCRs, proteases, ion channels, hormone nuclear receptors, kinases, and so on, to uncover novel members of these gene families. Choosing

Beyond the human genome sequence: functional genomics and bioinformatics

The challenge does not lie in finding and creating long lists of genes but in validating novel transcripts and picking winners for drug discovery early in the validation process. Various functional genomics platforms and approaches can be used to functionally characterize genes or reveal pathways. Most of them will require bioinformatics support for data management and analysis.

Conclusion

With the first draft of the human genome available, the identification of the majority of human genes is becoming a genuine possibility. Some of these genes will be similar to known gene drug targets; others will be completely novel. However, in most cases, functional analysis will be a necessity. Bioinformatics together with in silico analysis will play a major role in analysing, managing and connecting data to improve functional annotation using genomics methods. At present, computational

Acknowledgements

I thank colleagues from the Genome Informatics and Analysis Group at GlaxoSmithKline (Stevenage, UK) for their comments and suggestions.

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