organs and organisms, with their emergent proper-
ties that define the discipline of complex systems
biology.In vivocells operate in a dynamic and
communicative environment, where an effect of a
drugin one placemay welllead to correspondingor
compensatory changes elsewhere. The summation
of these innumerable responses often defeats the
predictions of high-throughput screens and three-
dimensional drug-receptor ‘design the key for the
lock’ calculations.
In vivotarget validation also still requires the use
of animal models. It is now possible to monitor
multipletargets within thesame cells byintercross-
ing independently derived strains of mice that have
been engineered to express different target genes
and/or to lack one or more target genes. These
models provide a powerful genetic approach for
determining specific events and signaling networks
that are involved in the disease process.
4.4 Other sources of compounds
Pharmacognosy is the science ofidentifying poten-
tial drugs that are naturally formed within plants or
animals. It is not yet an abundant source of mole-
cules, although The Pacific Yew did recently yield
paclitaxel for ovarian cancer. One large pharma-
ceutical company has concluded an agreement
with a Central American country to preserve its
entire flora and give the company exclusive rights
to any pharmacophores within it.
Combinatorial chemistry
The breakthroughs in technology that have allo-
wed sequencing of genes ‘on a chip’ and high-
throughput screening of compounds in microtiter
plate format have also caused a revolution in
chemical synthesis, known as combinatorial
chemistry.
Biological therapeutics
The chapter on biotechnology drugs enlarges on
this subject in more detail, but suffice it to say here
that vaccines, antibodies, proteins, peptides and
gene therapies all now exist. These biological
drugs bring with them specific, regulatory, clinical
trials and manufacturing difficulties. Gene therapy,
in particular, carries human safety risks that do not
apply to other classes of therapy, for example the
infective nature of some types of vector that are
employed, and the potential for incorporation of
the test genetic material into the genome in
males, leading to expression of gene products in
offspring.New uses for old drugs
Lastly, opportunities still exist for astute clinicians
to find new uses for old drugs, and for these newly
discovered uses to lead to new and unexpected
drugs. The recent approval of bupropion as a smok-
ing cessation agent is a good example of a chance
observation while the drug was being used for its
initial indication, which was as an antidepressant.
This has led to realization of the influence of nico-
tine on depression, and investigational drugs of a
new class, based on this alkaloid molecule, are now
being designed. Viagra is another good example of
a drug that was originally designed for one ther-
apeutic action and wound up becoming a blockbus-
ter drug in another therapeutic area.4.5 Summary
This chapter began with a survey of the modern
methods of drug discovery. Pharmaceutical physi-
cians should be aware of some of the techniques
employed and the rapid rate at which genetic infor-
mation is becoming available. It should be noted
that this modern revolution has not quite comple-
tely swept away the occasional new drug found by
serendipity or astute clinical observation.References
Amersham Life Science. 1993. Brochure on scintilla-
tion.Drug Discovery proximity assays. Publication
No. S 593/657/4/93/09. Amersham International.REFERENCES 49