Drug Discovery and Design How are drugs discovered and designed?

The ancestors of drugs – potions

Folk remedies – Aspirin Hippocrates IV cent. BC XVIII cent. AD Felix Hoffmann XX cent. Willow bark Powedered Willow bark Salicylic alcohol Salicylic acid Acetylsalicylic acid tea Salicin

Structure of aspirin carboxylic acid benzene ester

Preparation of aspirin Bitter Low fat solubility  poor absorption Better taste High fat solubility  higher absorption This reaction is reversed in the body

Your Turn. Similar structures, similar properties Approximately 40 alternatives to aspirin have been produced—with ibuprofen and paracetamol being the most familiar. Look at the structures of aspirin, ibuprofen and paracetamol. Identify the structural similarities and differences. Ibuprofen Aspirin Paracetamol

Look up the symptoms that each medication is advertised to treat Look up the symptoms that each medication is advertised to treat. Do you find any similarities or differences? Ibuprofen

Look up the top side effects for each medication Look up the top side effects for each medication. Do you find any similarities or differences? Ibuprofen Paracetamol Aspirin

Your Turn. You Decide : Supersize my aspirin A friend who suffers from heart disease has been told by the doctor to take one aspirin tablet a day. To save money, your friend often buys the large 300-tablet bottle of aspirin. You, on the other hand, rarely take aspirin, but cannot pass up a good bargain. You also buy the large bottle. Why is the “giant economy size” bottle of aspirin not as good a deal for you as it is for your friend? What chemical evidence supports your opinion?

One way to «discover» drugs

Lucky accidents - Penicillin The discovery of penicillin was a triumph of accident, a fortunate occurrence which happened while I was working on a purely academic bacteriological problem. – Alexander Fleming – Penicillium notatum Bacterial colonies Area of inhibited growth

Penicillium Area of inhibition Staphylococcus

Alexander Fleming (microbiologist) Ernst Boris Chain (biochemist) Sir Howard Walter (pathologist)

Penicillin – Mechanism of action cell wall

Modern drug discovery – rational approach and design

Mechanism of action of drugs Drug or hormone

Stage 1. Drug discovery Choose a drug target Identify a bioassay = a test used to determine biological activity Obtain compounds for screening

Stage 1. Drug design = optimization Goal: improve activity of active compound

Game 1

Game 2

Game 3

Stage 2. Pre-clinical development (250 compounds) Efficacy A > B

Drugs and poisons if > 4 g/day antileukemic

The dose makes the poison.

Stage 2. Pre-clinical development Efficacy (as for cells) + Safety Side effects Short- and long-term effects on specific organs/systems: Lethal dose

Animals and Drug Testing Consider This: Animals and Drug Testing Animal right groups often target the LD50 (lethal dose for 50% of the test animals) as an example of callous indifference to animal welfare. Other groups argue that such standards are necessary to insure drug safety and effectiveness. What is your position on the issue?

Stage 2. Pre-clinical development Pharmacokinetic properties Stability and shelf-life Formulation Scale-up Price

Stage 3. Clinical development (5 compounds) Efficacy and safety (as for mice) + Side effects

I’m going to give you a drug! Fake drug Feels better Feels better!!

(long-term toxicity)

Consider This: Double-Blind Study A friend of yours is dying from AIDS. He is in a hospital where a double blind study of a new anti-AIDS drug is being tested. By the nature of the test, he may or may not get the drug. What is your opinion about this research methodology? Would you be happy about your friend taking part in the study or do you think he should be given the test drug? Why?

Consider This: Who should pay? Streptokinase, a medication that dramatically increase the likelihood of surviving heart attack, costs 700 $ per dose. Who should pay for this life-prolonging drug–individuals, medical insurance, pharmaceutical companies, the government?

Consider This: A Lottery for Life? In early 1996, a lottery was held to select 2000 victims of advanced AIDS to receive an experimental drug called ritonavir. In other tests, similar drugs had proved effective in almost completely suppressing the AIDS virus in most subjects. Therefore, thousands of people suffering from the disease signed up for what might be a chance at prolonged life. Do you think this is a fair way of distributing a limited supply of the drug? What are your ethical arguments?