Week 5 Dr. Greig Lecture - Where do drugs come from? + placebo effect

Question 1

what is the super-responder effect

Answer 1

when given a drug some patients respond to it drastically and some get little effect, even when dealing with an intense disease, like cancer

ex. cancer treatment
- when a new cancer treatment is sent out some may be cured of their terminal cancer drastically and live for 20 + years and some may only live for three more years

Question 2

what is the placebo effect

Answer 2

the bodies ability to heal itself by believing a drug with little to no effect is healing them

Question 3

what are the chances of a drug going on the market after it enters clinical trials

Answer 3

1 in 20

but YOU HAVE TO DEFEAT OVERWHELMING ODDS TO GET TO THE 1 IN 20 CHANCE

Question 4

outline the unexpected odds of curing AIDS in a short amount of time

Answer 4

in 1981 = aids first reported - life expectancy is 1 year

2 years later = HIV identified as cause of AIDS

4 years later = the first drug cam out = increased life expectancy by about a year

8 years later = second class of drug came out against AIDS = when two classes were working to solve AIDS, chance of cure increased

12 years later = AIDS got a normal cure = Raltegravir = which caused individuals to obtain a normal life expectancy

Question 5

what is the Gartners hype cycle?

Answer 5

Peak of inflated expectations, trough of disillusionment, slope of enlightenment, plateau of productivity when a drug discovery is made

1. Naive euphoria
   - hyping drug when first discovered for many reasons including company investment
2. reaches a peak of hype
3. drops to depth of cynicism
   - when realized that the drug isnt life changing and wont change the world
4. true user benefits become apparent
   - people working on the drug find that the drug can still help and be a puzzle in the piece without changing the world
5. plateau as it finds role alongside existing technologies

Question 6

what is drug going to be like in 100 years in terms of finding and making a drug

Answer 6

• postulate: If we can understand it, we can cure it!

finding a drug target:
- Nowadays nothing is undruggable…all we need is a target and our amazing 22nd century technology will do the rest.

• We can test our bodies before and after a disease came to be to test the root of the problem

making the drug:
- We’ll be told what to make, how to make it…and then our robots will make it for us…resistance is (probably) futile

• ex. Chemputer as a modular desktop- sized robotic synthesizer, which
  ‘compiles’ text-based recipes into instructions to drive laboratory automation hardware.

Question 7

what are the two opposing views on drugs being art

Answer 7

• For many researchers, the process of creating drugs is an art and a science.
• Burke says that chemistry has
  become “an artistic expression of oneself through our molecule making”.
• Mimi Hii, director of
  Imperial College London’s Centre for Rapid Online Analysis of Reactions, argues that this is a
  bad thing. “Chemistry is a science, it shouldn’t be an art”
• Dr. Greig (prof) couldn’t disagree more…this makes drug discovery a soulless undertaking that doesn’t need humans – what about creativity, imagination, insight and gut feeling…are they unscientific…? Then most scientists are too!

Question 8

What are receptors examples of and some examples of how drugs work in the pathway (3)

Answer 8

Drug targets can be receptors
- usually sit on the outside of cells and it is waiting to pick up messages and translate it into actions
- ex. histamine can be the messenger when it reacts with the histamine receptor to activate various pathways and cause hayfever when in contact with pollen
- adrenaline –> adrenoreceptor -> fight or flight
- aceytlcholine –> muscarinic acetylcholine receptor -> rest or digest effect

Question 9

what is blocking and activation of receptors/drug targets

Answer 9

Either blocking or activating a receptor may have a therapeutic effect.
* Salbutamol activates an adrenoceptor and treats asthma
* Antihistamines like Benadryl block histamine receptors and control hayfever symptoms

Question 10

what are enzymes an example of and three examples?

Answer 10

enzymes can be drug targets too

ex. aspirin drug blocks cyclooxygenase enzyme and reduces headache

ex. statins –> blocks HMG Co-A reductase –> reduces cholestrol

ex. penicilin –> blocks transpeptidase –> reduces infection

Question 11

what is the target pathway in when a hormone binds to a cell and what could go wrong if not targeted properly?

Answer 11

normally:
- hormone binds and a bunch of pathways begin to reach dna to stop replication of mutant cell

however:
- sometimes, hormone binds and the cell replicates when it should not –> overactivation of cells –> leads to cancer

Any step can be targeted – but will it stop the disease or kill the patient?

Question 12

what is selectivity and why does it matter

Answer 12

what: when a drug binds to a selective receptor in the many types in that class it is said to be selective

why: if a drug effects all of the receptors then it can cause mishaps to the mechanism and cause a bouncing around of receptors

Question 13

what do we find easy and hard to do in terms of blocking messengers and proteins and whyyy

Answer 13

we find it easy to:
- block the messenger from binding to its target
why:
- most drugs are small
- if we want to cause this blockage, we simply make a drug that looks like the drug of choice so that it binds to its target before the actual drug does.
- ex. want to block histamine –> make a drug that looks like histamine and allow it to block before histamine can bind

we find it difficult to:
- block protein from binding to another protein or for protein to bind to the DNA
why:
- hard because we cannot imitate the surface of a protein or DNA

Question 14

What are characteristics of good and bad drugs in terms of binding sites

Answer 14

good drugs:
Good drugs have strong binding interactions with target.
Selective, so does not bind to other targets and thus are not toxic.
Binding site should be good pocket for the drug and unique (selective).

bad drugs:
Bad drugs have weak binding interactions with target.
Non selective, so is likely to bind to other targets and cause toxicity.
Bad drugs have flatter binding sites which can cause drug to mistakenly bond to many other areas on the target

Question 15

what is druggability? What are the 6 requirements?

Answer 15

a bioactive compound that can be used as a drug
- must have many unique properties to be a drug, but some of these properties may oppose the properties of another requirement:
1. Drug must dissolve in stomach - soluble

2. Drug must be absorbed from gut - move from the bloodstream
   - this requires opposite properties than that of solubility
3. Drug must survive the liver and the body’s attempts to destroy it
   - body tries to destroy it when it is identified as an alien substance
   - substances that pass through gut wall easily are the types of substances that can be chopped up easily by the liver
4. Drug must not affect other parts of the body
   - no good if the drug that tries to cure your headache, speeds up your heart
5. Enough of the drug must reach the brain
   and get through the protective barrier around the brain
   - this protective barrier is very strong so hard for substances that are soluble to easily pass through
6. Drug must now bind to target
   - for sufficient amount of time and quantity

Question 16

are all targets druggable? what are the biggest challenges

Answer 16

not all targets are druggable

biggest challenge is the flat surface of weak binding between the drug and the protein or DNA

Question 17

what does our future look like with all these challenges in drug creation

Answer 17

we will not find it difficult in 100 of years
- we will be able to break up the interaction between two proteins and protein and dna with a compound that can survive all the conditions

Question 18

what are current challenges to drug synthesis (5)

Answer 18

• Often we don’t understand the cause of a disease (e.g. Alzheimer’s) and cannot find clear differences between sufferers and healthy individuals
• Frequently a single target is only part of the story and hitting it alone will not cure the disease
• The ideal disease target may be essential to other aspects of our health
  …and we still cannot design and make the right drugs to hit every target
• lack of computational power – we only see a snapshot of a drug and a target, not their interaction

Question 19

why is drug discovery so difficult? In terms of adventure in body

Answer 19

polar drugs dissolve in stomach gut (solubility)

Lipophilic drugs better absorbed from the gut (permeability)

Polar drugs less likely to be metabolised in the liver

Lipophilic drugs are able to pass the blood brain barrier

Polar drugs less likely to hit other targets

Lipophilic drugs are less likely to be cleared by the kidneys

Question 20

what properties does a druggable target need to pass through the body’s system?

Answer 20

If our target is too polar or too lipophilic then it may be impossible to find a drug that can actually get to it (may not be soluble, permeable, stable etc)

A “druggable” target will need to have a mixture of lipophilic and polar residues in order for us to develop a drug that will be able to reach it

Question 21

what was the notion of drug discovery in the 1900-2000s

Answer 21

drug discovery was primarily evolutionary
* Develop new drugs from what we already have
* Develop new drugs from what we already know
* Get lucky
* Talented people free from corporate interference

idea of low hanging fruit and a blank canvas:
* Many diseases with no treatments
* Any small beneficial effect on a disease is worthwhile
* Anything you make is novel and potentially exciting
- essentially drug discovery was easy because not many things have been discovered.

Question 22

what do chemical dynasties show us?

Answer 22

the lineage and generations of a drug can be tracked and dated to a parent drug. these may have different properties but stem from the same drug. they also may be used for different purposes even though they have similar chemical structures.

ex. methylene blue stems the onset of many drugs
- one generation later it creates sedative antihistamines
- 3 generations later it creates non-sedative histamines
- in the middle it is altered to create drugs for schizophrenia, nausea, depression etc.

Question 23

How could we create new anti-histamines that block the receptor?

Answer 23

idea: use what the body normally uses (endogenous ligands and substrates)

• Histamine causes itchiness and stomach ulcers (via acid release)
• Antihistamines only stop itchiness not ulcers
• There must be more than one type of histamine receptor (H1 and H2)
• We know histamine binds to H2 and turns on the receptor.
• Maybe if we modify histamine, it will still bind but no longer activate it (ie. block it)

we found that:
* histamine: is a H1/H2 agonist and causes itches and release of stomach acid causing ulcers

• burimamide, a variation of histamine, was a low potency (ie. not great) H2 antagonist
• Cimetidine, a variation of burimamide, was a high potency H2 antagonist that threats stomach ulcers.
  it blocks the receptor by binding but doesn’t activate it

Question 24

how could we create new adenaline substrates that only bind to the lungs not anywhere else?

Answer 24

idea: the adrenoceptors (a1, a2, β1, β2 and β3) are all slightly different shapes and sizes
– subtle changes to the shape of adrenaline = selectivity

what we know
- adrenaline is a non selective activator and causes fight or flight
- salbutamol is a beta type receptor activator and is a bit bigger in the lungs –> cures asthma
- Phenylephrine is an alpha-type receptor activator that is small, and can cure a blocked nose
- Propranolol is a β-type receptor blocker and is bigger, so when blocked can reduce hypertension, angina and heart failure

Question 25

what is the best natural product to help with mechanisms in your body?

Answer 25

your body itself – not rainforests or underwater environments

Question 26

how has nature evolved to help eliminate diseases?

Answer 26

• natural sources can be the answer to every disease
• these natural and folk sources is still used by 80% of the world population
• nature has evolved to select for certain active compounds and biological processes
• but this selection is to kill foreign species like antibiotics or cancer

Question 27

what is the problem with using natural sources to help cure diseases?

Answer 27

even if the answer for a disease is out in the natural world, the problem is finding a suitable lead:
- randomly screening every plant, marine or soil sample and then finding an active principle is not suitable.
- ethnopharmacology: we may think some folk remedies have truth to it because it has been used for so many years, however, thats not necessarily the truth

Question 28

what is a con in identifying active principles?

Answer 28

can be extremely time consuming.
due to:
- extraction, seperation, and purification
- even when we do this, we may find that the active principle relies on some synergism between various components and that each may have only very weak activity
- it may not be feasible to obtain sufficient quantities from the original source and yet the active principle may be too complex for laboratory synthesis to be a realistic option (Ex. Taxol)

Question 29

what is taxol

Answer 29

• might revolutionize the treatment for certain types of cancer
• taxol stops cancer cells from dividing and growing
• extracted from the bark of a mature Pacific Yew tree
• to treat one patient it may take the bark from 3 x 100 year old trees
• making taxol is very valuable: discovery made $350 million for FSU

Question 30

explain the mishap of obtaining Halichondrin B

Answer 30

Halichondrin B showed potential to cure certain types of cancer
- it is produced by black natural black goo
- however, it was not possible to obtain enough from natural sources
- but, positively, they found that you don’t need all of the Halichondrin B compound to make the cure for certain cancers
- unfortunately, obtaining that small bit is very difficult and it takes 90 steps in the lab to obtain
- eventually got it down to 68 reaction steps in the lab
- unfortunately, this means it is very expensive and thus was rejected in the UK.

Question 31

what is the ultimate example of a natural product

Answer 31

insulin!

Question 32

why was insulin revolutionary

Answer 32

• before insulin, the life expectancy for those with type 1 diabetes from diagnosis was less than a year – even that was if you were on a starvation diet
• Frederick Banting and Charles Best discovered it on the at the University of Toronto’s Medical Building in 1922

Question 33

what is the benefit of natural resources that makes it so innovative

Answer 33

• Nature is extremely good at suggesting starting points for a study and identifying lead compounds
  which may then be developed, if over a period of many years to give a highly potent new drug.
• Nature is still capable of producing compounds which no chemist would even have dreamed could even exist
  – e.g. penicillin and artemisinin (for malaria).

Question 34

what are stats of natural products

how many drugs are natural products, modified natural products, and mimic natural products

Answer 34

• 6% of drugs are natural products
• 28% are modified natural products
• 30% mimic natural products

Question 35

what does serendipity mean

Answer 35

when someone is lucky because of chance but is well prepared to manage that luck for benefits

Question 36

what is the example of serendipitous drug, Viagra

Answer 36

Viagra is a serendipitous drug for the treatment of erectile dysfunction

initially it was manufactured for the treatment of angina a cardiovascular condition.
It was failed for this condition, but patients still wanted to keep the drug because of its side effects for erectile dysfunction.

Question 37

what is the history of thalidomide and how was it lucky and unlucky in history?

Answer 37

• was made to help morning sickness associated with pregnancy
• it famously was not approved by the FDA but was accepted in other countries
• rightfully so because it caused defects in developing embryo in the pregnant woman
• the drug was withdrawn from the market
• however, later a patient with Leprosy, a skin disorder, and desperately needed a drug to help
• the patient tried thalidomide because it was the only drug left on the shelves
• found that is cured his skin disorder
• found later that it could be used for multiple myeloma, skin cancers