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.