The mapping of the human
genome should help!
• In the past, many medicines (and lead
compounds) were isolated from plant sources.
• Since plants did not evolve with human beings in
mind, the fact that they posses chemicals which
results in effects on humans is incidental.
• Having the genetic code for the production of an
enzyme or a receptor may enable us to overexpress that protein and determine its structure
and biological function. If it is deemed important
to the disease process, inhibitors (of enzymes), or
antagonists or agonists of the receptors can be
prepared through a process called rational drug
design.
Simultaneously, Chemistry is Improving!
• This is necessary, since,
ultimately, plants and natural
sources are not likely to
provide the cures to all
diseases.
• In a process called
“combinatorial chemistry”
large numbers of compounds
can be prepared at one time.
• The efficiency of synthetic
chemical transformations is
improving.
Selectivity is Important!
• e.g. targeting a bacterial enzyme, which
is not present in mammals, or which has
significant structural differences from
the corresponding enzyme in mammals
The Standards are Being Raised
• More is known about the biological
chemistry of living systems
• For example: Targeting one subtype of
receptor may enable the pharmaceutical
chemist to avoid potentially troublesome
side effects.
Problems can
arise
• Example: The chosen target, may over time, lose
its sensitivity to the drug
• Example: The penicillin-binding-protein (PBP)
known to the the primary target of penicillin in the
bacterial species Staphylococcus aureus has
evolved a mutant form that no longer recognizes
penicillin.
Choosing the Bioassay
• Definitions:
– In vitro: In an artificial environment, as in a test
tube or culture media
– In vivo: In the living body, referring to tests
conductedin living animals
– Ex vivo: Usually refers to doing the test on a
tissue taken from a living organism.
Choosing the Bioassay (cont.)
In vitro testing
• Has advantages in terms of speed and requires
relatively small amounts of compound
• Speed may be increased to the point where it is
possible to analyze several hundred compounds
in a single day (high throughput screening)
• Results may not translate to living animals
Choosing the Bioassay (cont.)
In vivo tests
• More expensive
• May cause suffering to animals
• Results may be clouded by interference
with other biological systems
Finding the Lead
Screening Natural Products
• Plants, microbes, the marine world, and
animals, all provide a rich source of
structurally complex natural products.