Introduction To Drug Discovery

How are drugs discovered and developed ?

Choose a disease Choose a drug target Identify a bioassay bioassay = A test used to determine biological activity.

Find a lead compound lead compound = structure that has some activity against the chosen target, but not yet good enough to be the drug itself. If not known, determine the structure of the lead compound

Synthesize analogs of the lead Identify Structure-Activity-Relationships (SARs) Synthesize analogs of the lead Identify Structure-Activity-Relationships (SARs)

Identify the pharmacophore pharmacophore = the structural features directly responsible for activity Optimize structure to improve interactions with target

Determine toxicity and efficacy in animal models.

Determine pharmacodynamics and pharmacokinetics of the drug. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug.

Patent the drug Continue to study drug metabolism Continue to test for toxicity

Design a manufacturing process Carry out clinical trials Market the drug

Choosing a Disease
Pharmaceutical companies are commercial enterprises Pharmaceutical companies will, therefore, tend to avoid products with a small market (i.e. a disease which only affects a small subset of the population)

Choosing a Disease
Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries)

Choosing a Disease (cont.)

Most research is carried out on diseases which afflict first world countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine, obesity).

Identifying a Drug Target

Drug Target = specific macromolecule, or biological system, which the drug will interact with Sometimes this can happen through incidental observation

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

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 conducted in 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.

It is necessary to have a quick assay for the desired biological activity and to be able to separate the bioactive compound from the other inactive substances Lastly, a structural determination will need to be made

Finding the Lead (cont.)

Screening synthetic banks Pharmaceutical companies have prepared thousands of compounds These are stored (in the freezer!), cataloged and screened on new targets as these new targets are identified

Finding the Lead (cont.)

Using Someone Elses Lead

Design structure which is similar to existing lead, but different enough to avoid patent restrictions. Sometimes this can lead to dramatic improvements in biological activity and pharmacokinetic profile. (e.g. modern penicillins are much better drugs than original discovery).

Use structural similarity to a natural ligand

NH2 H N H3C O N H 5-Hydroxytryptamine (5-HT) Serotonin (a natural neurotransmitter synthesized in certain neurons in the CNS) S O N H Sumatriptan (Imitrex) Used to treat migrain headaches known to be a 5-HT1 agonist

N(CH3)2

HO

Toxicity Toxicity standards are continually becoming tougher Must use in vivo (i.e. animal) testing to screen for toxicity
Each animal is slightly different, with different metabolic systems, etc. Thus a drug may be toxic to one species and not to another

The endangered lizard's poison stimulates the body's production of Insulin.

It can prevent blood sugar levels from dipping perilously low, or stop it from
spiking and causing damage to the liver, kidneys, eyes and limbs In 1992, Eng's studies revealed that the venom contained two compounds, including one that had never been documented. He named it Exendin-4.

The compound seemed to have properties similar to a human gut hormone, GLP-1, that was being researched around that time by scientists at Massachusetts General Hospital. GLP-1, however, is that enzymes in the blood cause it to degrade quickly

Mile Stones
American Diabetes Association annual meeting in San Francisco
In October 1996, Eng licensed his discovery to Amylin

Then in 2002, Lilly gave Amylin a $325 million shot in the arm by agreeing to work with the biotech company on exenatide.
"It really is a beautiful lizard," Eng said. "Like many other animal species it is under pressure from development and other environmental concerns. "The question is, what other animal has something to teach us that can be of future value? And plants, too? We will never know their value if they are gone."

The END