Model Organisms in Drug Discovery

INTRODUCTION TO COMPOUND DEVELOPMENT 155
error’ clinical trials, the doctors (or shaman) would try different combinations
of drug extracts. These extracts would have one of three different effects:
nothing would happen, in which case a different combination of extract would
be applied; the patient would get sicker, in which case the dosage would be
stopped; or the patient would show some kind of improvement or effect that
would be noted for the future. Often, the effects of plant extracts were
hypothesized by acute observation of animal behavior or the effects of such
plants or animal venom on wildlife. This type of drug discovery is still
underway in large populations of people in the world, and over thousands of
years through trial and error several combinations of plant extracts have been
found to alleviate some human diseases and their symptoms. Most often in
these cases the individual efficacious component of the complex plant extract
has been (and often remains) unknown. Therapies that have been developed in
this fashion continue to be sold today and are generally referred to as herbal
remedies or ‘natural products’.
During the 1970s a large portion of pharmaceutical drug discovery was
devoted to separating the individual components of plant and animal extracts
in the search for the active compound(s). These extracts would be applied to
cell-based assays with readouts designed as surrogates for disease endpoints.
Compounds that produced an effect were progressed forward into drug
discovery and animal models. In most of these cases the target protein(s)
whose activities were being modified by the compounds in the extract
remained unknown. A good example of this type of drug discovery was the
advent of the diabetes drugs thiazolidinediones, in which the target was
unknown for many years (now known to be peroxisome proliferator-activated
receptors, PPARs) (O’Moore-Sullivan and Prins, 2002). Another example in
the same disease area occurs with the compound metformin, which has been
used in the treatment of diabetes for decades and yet whose MOA remains
undefined (Sirtori and Pasik, 1994). Additional compounds discovered in this
way include parthenolide, digoxin, salicylic acid, opium, tropane alkaloids,
galantamine and camptothecin, the active ingredients of Feverfew, Foxgloves,
Willow bark, Poppy seeds, Snowdrops and Happy tree, respectively (Bynum,
1970; Heptinstall, 1988; Wall and Wani, 1995; Brune, 2002). The early
methods of drug discovery had many shortcomings and were very inefficient.
Natural products tend to be complex molecules that can be difficult to
synthesize de novo. In addition, if a compound discovered through natural
product separation has undesirable properties, such as solubility or
pharmacokinetic issues, it is impossible, without knowing what the protein
targets of the compound are, to find a new chemotype with similarly
efficacious properties and the same MOA.
In the early to late 1980s with the advent of molecular biology, the
understanding of basic biology exploded and recently has been combined with
the knowledge of the human genome. In parallel to the innovations in biology,