TBL 1 - DRUG DEVELOPMENT AND SOURCES OF DRUGS

Question 1

In what century were there accidental discoveries of pharmaceutical actions?

Answer 1

Before 20th century medicines herbs/potions -pharmacological actions found accidentally and toxicities ignored..

Question 2

When did medicinal products become isolated and purified?

Answer 2

Mid 1800s effort made to isolate/purify chemicals responsible for medicinal products.

Question 3

What are the 3 naturally occurring drugs that have been isolated/studied?

Answer 3

Naturally occurring drugs isolated/studied:
1) Morphine from opium
2) Cocaine from coca leaves
3)Quinine from bark of cinchona tree

Question 4

How long does it take to design/develop a drug and how much will it cost?

Answer 4

• Design/development of drug takes 15 YEARS.
• Synthesis of 10,000 compounds
• Cost - $2 bil

Question 5

Who does drug development need approval from in both the US and EU?

Answer 5

Drug development needs approval from agencies before becoming an official drug and are able to supply and market the drug. In US - FDA (food and drug administration), in Europe it’s the EMA (European medicines agency). Pharmaceutical companies have to submit applications around the world and base their decisions on the outcome of submissions to agencies.

Question 6

What happens in the first 3 to 6 years of drug development?

Answer 6

Drug discovery: 5000-10000 compounds
Preclinical: 250

Question 7

What happens in the 6-7 years of drug development?

Answer 7

Clinical trials:
Phase 1: Number of volunteers 20 to 100
Phase 2: Number of volunteers 100 to 500
Phase 3: Number of volunteers 1000 to 5000

Question 8

What happens after clinical trials during drug development?

Answer 8

• Takes 0.5 to 2 years for FDA approval

Question 9

What happens after the drug is developed?

Answer 9

Post-Marketing surveillance

Question 10

Why is the research process done?

Answer 10

Research process is the continuous optimizations process where the goal is to seek out the BEST MOLECULE which has all the DESIRED PROPERTIES required for a PARTICULAR DISEASE.

Question 11

What is Biological target identification?

Answer 11

• Disease caused by process in body that’s stopped working, has deviated from the original purpose or became overactive. - occurs when protein becomes up-regulated, down-regulated or became overactive
• Researchers work to identify the proteins for the purpose to see if the disease can be controlled or cured if the protein can be targeted by a suitable drug substance.
• Biological target won’t be valid until successful trails undertaken.

Question 12

What is an example of biological target identification?

Answer 12

Targets can be chosen to follow the discovery of the mechanism of action of other drugs.
For example:
- Tricyclic antidepressants such as desipramine were known to exert their biological effect by inhibiting the uptake of the neurotransmitter noradrenaline from nerve synapse.
- Drugs also inhibited neurotransmitter called serotonin, was postulated that this might be beneficial.
- Searches for selective serotonin uptake inhibitor led to fluoxetine (Prozac) - best-selling antidepressant drug.

Question 13

Which diseases has advantages to developing compound which interacts with variety of biological targets?

Answer 13

For example:
- Olanzapine (which is used in the treatment of schizophrenia) has been highly effective.
- Olanzapine binds to receptors for serotonin, dopamine, muscarine, noradrenaline and histamine.
- Promiscuity of drug usually unacceptable but olazapine is successful, as it blocks both serotonin and dopamine receptors.
- Lack of specificity towards single target usually problem as results from numerous off-target toxicities

Question 14

HTS (high throughput screening) is a technique used for hit molecule identification how is it used?

Answer 14

Thousands (millions) of compounds held in compound banks in pharmaceutical companies are assayed against target of interest to see if any molecule interact with this protein.

Question 15

Natural products is a technique used for hit molecule identification how is it used?

Answer 15

Purified organic compounds isolated from natural sources that are produced by the pathways of primary or secondary metabolism. Have no essential biological responsibility in host organism, leads to enhanced survival traits.

Question 16

What are the 5 examples of Natural product sources?

Answer 16

1) Plant kingdom: e.g. morphine, cocaine, digitalis, quinine, tubocurarine, nicotine and muscarine.
2) Microorganisms: e.g. penicillin, cephalosporins, tetracyclines, rifamycin’s, chloramphenicol and vancomycin (antibacterial)
3) Marine sources: e.g. eleutherobin, byostatins, cephalosporins and halichondrin B (used as antitumor agents)
4) Animal sources: e.g. epibatidine (potent anaglegesic)
5) WVenoms and toxins

Question 17

Medical folklore is a technique used for hit molecule identification how is it used?

Answer 17

Most treatments didn’t work, but had some therapeutic value.

Question 18

What is an example of medical folklore?

Answer 18

For example:
Rhubarb root used as purgative for many centuries - discovered anthraquinones, present in the roots, were responsible for this effect which lead to the discovery of the laxative dantron.

Question 19

Natural ligands is a technique used for hit molecule identification how is it used?

Answer 19

Biological molecules which naturally interact with the protein can be modified chemically to generate new hits.

Question 20

What is an example of natural ligands?

Answer 20

For example:
Adrenaline and noradrenaline were the starting point for the development if adrenergic B-agonist such as salbutamol, dobutamine and xamoterol.

Question 21

Existing drugs is a technique used for hit molecule identification how is it used?

Answer 21

There may already be drugs on the market which interact with protein but would require some modification.

Question 22

What is an example of existing drugs?

Answer 22

For example:
- Have a compound which has ideal properties for oral absorption but to avoid toxic effects an inhaled compound would be more effective.
- Oral/inhaled drugs don’t share same physiochemical properties.
- Company not allowed to market same compound which has the same identical structure as another company, unless patent protection has expired - becomes a generic product but may market a compound with the same biological target.

Question 23

Serendipity is a technique used for hit molecule identification how is it used?

Answer 23

• WW2, US ship carrying mustard gas exploded survivors who inhaled gas lost their white blood cells and their natural immunity against microbes.
• Mustard gases optimized to give treatments for leukemia, a condition which results in the excess proliferation of WBC.

Question 24

Development of hit molecule to lead molecule:

Answer 24

Hit compounds identified chemists work to synthesize analogues of these to build up a picture which aspects of molecules for activity (structure-activity relationships or SARs)

Question 25

What is an example of SAR (structure-activity relationships)?

Answer 25

Example of SARs: structure of opioids when compared to morphine.

Question 26

What is Lead molecule optimization?

Answer 26

Further optimisation and synthesis of analogues will result in the identification of up to 5 molecules which exhibit all the desired properties required. This may be a compromise and often this molecule will not be perfect but will have an acceptable balance between potency and desired physical properties. Hundreds of compounds may be synthesised during this stage,

Question 27

In the pre-clinical safety what is the investigation focus on?

Answer 27

Where molecule is selected for PCS (pre-clinical safety). - focus to investigate if candidate has any toxicity.

Question 28

In pre-clinical stage what is first tested on to check the drugs effect

Answer 28

Start in vitro tests on cells and/or in-vivo tests on animals to investigate if compound has any effect on cell reproduction and identify potential carcinogens which would prevent any further development of the candidate.

Question 29

How are a drug toxicity checked in the pre-clinical stage?

Answer 29

• Drug tested for acute toxicity by administrating large doses to find out toxic level may be. - animals used/dissected to test whether particular organs affected.

Question 30

How do you check for chronic toxic effects in the pre-clinical stage?

Answer 30

Long term toxicity test in animals will be carried out over a period of years to test the drug for chronic toxic effects.

Question 31

What is an examples of a drug that failed toxicity test?

Answer 31

An example of Drug that failed toxicity test:-
- Antifungal agent (UK 47265) which was an antifungal was discovered in PCS to be potentially teratogenic.

Question 32

What does toxicity studies help to indicate?

Answer 32

Toxicity studies help to indicate the safe doses to be used later in human trials.

Question 33

Why are drug metabolism studies carried out?

Answer 33

Drug metabolism studies carried out where compound will be subjected to enzymes responsible for the breakdown of drugs in the body.

Question 34

What another things are investigated during the pre-clinical safety stage (PCS)?

Answer 34

API and excipients investigated in the PCS stage for effectiveness and stability.

Question 35

What agencies approve drugs?

Answer 35

Approval for drug for humans needs to be granted by a regulatory body e.g FDA OR EMEA.

Question 36

Where are adverse reaction during the PCS reported?

Answer 36

Any adverse reaction during the clinical trials will be reported to the regulatory body.

Question 37

When drug finished what type of application is sent to FDA and EMEA?

Answer 37

Trial proceeds smoothly new drug application (NDA) to FDA and marketing authorisation application to the EMEA is made..

Question 38

Why are orphan drugs fast tracked?

Answer 38

Orphan drugs fast tracked. Orphan drugs are new treatments for diseases which have no-existing treatments.

Question 39

When can clinical trails start?

Answer 39

Once PCS assessments determine that drug is not toxic to humans and regulatory approval has been obtained, clinical trials can start.

Question 40

Before a drug can be prescribed what does NICE have to carry out?

Answer 40

Drug that is licensed and before it can be prescribed in the UK - a cost vs benefit analysis carried out by NICE. Decide whether NHS should pay for drugs and determine if they can be prescribed to patients.

Question 41

What is an example of a drug that was not approved by NICE?

Answer 41

Some anticancer drugs not approved by NICE - e.g. breast cancer drug kadcyla.

Question 42

One way in which computer technologies can support drug development:

Storing chemical information:

Answer 42

1) Storing chemical information:
Amount of info attributed to a single chemical compound is huge for a single chemical info gathered into areas like:
- CHEMICAL IDENTITY
- CHEMICAL PROPERITES
- SYNTHESIS/ANALYTICAL

• Most effective approach to store data in an electronic chemical database so they can be easily organized, searched and retrieved.
• Database developed within pharmaceutical companies for internal use only and compile research data.

Question 43

What is chemspider?

Answer 43

Chemspider:
- Database for chemical structure and:
- Common names, trade names, chemical names, IUPAC names…

Question 44

Second way in which computer technologies can support drug development (5 things):

Computational libraries and computer-aided drug design

Answer 44

2) Computational libraries and computer-aided drug design:
1) Database of chemical compounds and their activities.
2) Activities can be potency to therapeutic target or adverse drug reactions.
3)Computational libraries allow users to construct different quires to find out what info is already known to help them.
4)Most drugs work by blocking or triggering activity a specific protein, another cheminformatics approach is to build a detailed computer model of protein target and investigate the binding of the natural ligand.
5)Design a drug can bind to target in a similar manner.

Question 45

Third way in which computer technologies can support drug development (5 things):

Virtual screening to select possible lead compounds:

Answer 45

3) Virtual screening to select possible lead compounds:
- Computational models of targets used for designing drug to mimic natural ligand.
- Molecular docking or virtual screening: binding site of protein known as computational model used to screen compounds for their ability to fit these ligand requirements.

Question 46

Fourth way in which computer technologies can support drug development (5 things):

Molecular modelling to predict drug properties, activities and toxicities:

Answer 46

4) Molecular modelling to predict drug properties, activities and toxicities:
It is possible to predict various physicochemical properties of compounds directly from their chemical structure. It is also possible to predict their activity and other properties (including ADMET profile) in a similar manner. This can be termed molecular modelling.

Question 47

What are advantages of chemoinformatic approaches (7 things)?

Answer 47

1) Low cost
2) Fast
3) Can be preformed of knowledge of structure alone (pre-synthesis)
4) Reduces the number of labatory animal used in testing
5) Rapid identification/ranking of possible lead candidates
6) Unsuitable candidates can be rapidly eliminated (fail fast, fail cheap)
7) Ability to handle huge amounts of data

Question 48

What are disadvantages of chemoinformatic approaches (4 things)?

Answer 48

1) Predictions can sometimes be inaccurate
2) Need to develop/buy a suite of predictive model
3) Complex software can restrict users
4) Chemoinformatic is not a standalone approach but a complimentary technology

Question 49

Fifth way in which computer technologies can support drug development (5 things):

Answer 49

5) Finding new uses for existing drugs:
- Cheminformatics is not only concerned with developing new drug molecules.
- Given the huge cost and time that needs to be invested in developing new drugs, efforts are also turned towards finding new uses for existing drug compounds (sometimes termed repositioning).
- Utilising new knowledge of drug targets and mechanisms of action for certain diseases, it is possible to use the chemoinformatic database tools and virtual screening technologies to identify existing drugs that may act as possible treatments.
- Example: Topiramate. This is an anticonvulsant used in the treatment of epilepsy. However, it has subsequently emerged as a possible treatment for inflammatory bowel disease.
- majority of pharmaceutical companies use cheminformatics throughout the drug development process not only to find potent drugs, but also to identify possible toxicities.
most of the large pharmaceutical companies have dedicated computer modelling departments to support drug development.