Summary
In recent years, the process of drug discovery has changed immeasurably. It
has gone from a process that was largely disease-focused to one that is
target-led. This change has been driven by a number of factors, among
them technological advances and economic pressures.
Under the old paradigm, drug discovery began with the identification of a
human disease and the development of an animal model of it. Chemical
compounds that ameliorated the animal disease were then used as the
starting point for the development of a new therapeutic substance. The
present approach focuses very much on the identification of potential drug
targets, which are typically individual genes or gene products. If the gene
underlying a particular disease can be identified, the reasoning goes, then
the discovery of chemical compounds or biological agents that modulate the
targets, and therefore hopefully treat the disease, can be automated, which
is vastly more efficient than dealing with animal models.
However, not everyone agrees that this genetic reductionist approach is
valid. While it appears superficially attractive, a number of objections, both
theoretical and practical, have been raised. Nevertheless, it has been widely
embraced by the pharmaceutical industry.
This report provides an overview of the concept of drug targets, and
discusses their place in modern drug discovery. It looks at the role of
technologies such as genomics, proteomics and bioinformatics in target
identification, as well as describing the downstream processes such as target
validation, lead discovery, lead optimisation and clinical development. It also
discusses the various types of drug targets using specific examples where
appropriate.
Chapter 1 provides a historical perspective to drug discovery, looking briefly
at the pioneering work of researchers such as Ehrlich, Domagk, Fleming,
Ahlquist and others. Using specific examples, it discusses the development
of receptor theory, describes the role of second messengers in mediating the
effects of drugs, and shows how the concept of drug receptors was
gradually overtaken by an appreciation of targets in the wider sense.
Chapter 2 discusses the changes in drug discovery techniques that came
about during the closing years of the 20th century. Advances in genetics,
particularly functional genomics and the Human Genome Project have
revolutionised the way that drugs are discovered, and these techniques are
discussed in that context. Chapter 2 also looks at the processes of target
validation, lead discovery and optimisation, preclinical development and
clinical development.
Chapter 3 focuses on drug discovery in the post-genomic era. It describes
benefits that genomic and post-genomic sciences promise to bring to the
process of drug discovery, and discusses some of the criticisms levelled
against the genetic reductionist approach to drug discovery. The Human
Genome Project revealed far fewer genes in the human genome than had
been supposed, and Chapter 3 assesses the implications of this for drug
discovery, asking just how many potential targets there are concealed within
the human genome.
Chapter 4 looks specifically at the major types of drug target: DNA, nuclear
receptors, enzymes, ion channels, receptors, and hormones and factors. In
each category, the report provides a classification of drug targets, describes
some of the techniques used to study them, and gives examples of current
R&D in that particular area.
Finally, a series of appendices provides case-studies illustrating the use of
genomics data in the identification of drug targets and how an enzyme
target might be used in drug discovery.
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