The mapping of the human genome should help!

1
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.

2

• Having the genetic code for the production of an
  enzyme or a receptor may enable us to
  over-express 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.

3
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.

4
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

5
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.

6
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.

7
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.

8
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

9
Choosing the Bioassay (cont.)

• In vivo tests
• More expensive
• May cause suffering to animals
• Results may be clouded by interference with other
  biological systems

10
Finding the Lead

• Screening Natural Products
• Plants, microbes, the marine world, and animals,
  all provide a rich source of structurally complex
  natural products.