Drug design and discovery

Question 1

What is a drug?

Physiological

Answer 1

• A chemical substance used to prevent or cure disease
• A substance which has a physiological effect when introduced into the body

Question 2

What are the developments in drug discovery?

Characterize, observe

Answer 2

• We can do chemical synthesis
• Can make almost any compound
• Can modify compounds
• We know the structure of compounds
• Can characterize compounds fully
• Can observe in really precise detail what they do in biology and what biology does to them and how they effect cells.

Question 3

What does an assay do?

Answer 3

Helps decide what drugs are or arent working.

Question 4

What are hit compounds?

Answer 4

When the drugs have been narrowed down to the ones that work okay.

Question 5

What can we get from natural products?

Answer 5

Unusual products that we might not make in the lab

Question 6

What is the main difference between traditional and modern medicine?

Constituents

Answer 6

• The main difference between traditional medicine and modern medicine is that we now have the tools to test how well treatments actually work.
• We can also now separate all the constituents of any particular extract

Question 7

What are the benefits of natural products?

Biotech, diverse

Answer 7

• All natural products have some kind of biological activity already
• Could be produced by agricultural or biotechnological methods
• Provides access to unusual/diverse structures

Question 8

What are the drawbacks of natural products?

total

Answer 8

• Can be difficult to obtain in high yields
• Total synthesis challenging
• Compounds are not optimised so need to be modified
• Could be allergens

Question 9

What is phenotypic screening?

Hypothesis

Answer 9

Approaches looking only at the final effect of a drug, rather than relying on knowledge/hypotheses of how the drug works

Question 10

How can you make a molecule fit a particular target?

ES or molecule

Answer 10

• A variation of the molecule that the target binds to in nature (either the enzyme-substrate or the molecule which binds to a receptor)

Question 11

What is docking?

Answer 11

• Calculate where and how well a molecule binds to the target.
• Often using a large virtual library of compounds which could be synthesised.

Question 12

What is a binding site map?

Answer 12

Creating a model illustrating what arrangement of intermolecular interactions can be addressed.

Question 13

What is de novo drug design?

Answer 13

Ask the computer to generate a molecule which could bind in the chosen site

Question 14

What happens if you create a binding site map?

Answer 14

You end up with something very generic and have to find a way to connect the fragments in a way that is synthetically accessible.

Question 15

What are the benefits of designed synthetic compounds?

Mechanism

Answer 15

• Synthesis straightforward (comparatively)
• Readily modified at any point to tune properties
• Mechanism of action usually well understood

Question 16

What are the drawbacks of designed synthetic compounds?

Answer 16

• Limited to molecules which are easily made
• Chirality and larger 3D structures rarer
• Does not work so well on proteins without small molecule binding pockets

Question 17

What do you do in screening?

Assay

Answer 17

Measure each molecule’s interaction with the molecule using well plate based assays

Question 18

What do you do in selection?

Affinity

Answer 18

Use some affinity measurement to separate binders from non-binders.

Question 19

What are oligomers?

Answer 19

Chains but not necessarily peptides

Question 20

What are the benefits of selection?

Answer 20

• Test millions of molecules at once
• Could uncover unexpected activities
• Exploit molecular biology techniques – phage display of peptides, PCR, sequencing, etc.
• Target any protein with larger molecules

Question 21

What are the drawbacks of selection?

Answer 21

• Might not find any good hits – even a library of >1 million compounds could be poorly designed
• Limited to libraries which can easily be made
• Larger molecules may have trouble getting through membranes etc.

Question 22

What is in vitro?

Answer 22

On isolated cells, tissues and proteins

Question 23

What is in vivo?

Answer 23

Entire organisms

Question 24

For biological assays, is in vitro or in vivo preferred and why?

Answer 24

In vitro is usually preferred for initial tests because it is cheaper, quicker, less controversial, and can be automated.

Question 25

What does in vitro test for?

Answer 25

This will test whether the drug engages its target, in what fashion, whether it changes the target’s activity, and whether it kills cells.

Question 26

What are in vivo tests used for?

Answer 26

• In vivo tests will be performed on a smaller selection of compounds – on mice, and potentially other animals.
• They will uncover information about systemic toxicity, absorption, distribution, metabolism, and excretion (ADME).

Question 27

What is hit-to-lead?

Answer 27

Hit-to-lead: compounds from the library are short-listed according to:
- Synthetic accessibility
- Specificity
- Toxicity
- Physical properties

Question 28

What is lead optimisation?

Answer 28

Lead optimisation: the compounds will be optimised for:
- Physicochemical properties (polarity, HBs, molecular weight)
- ADME
- Toxicity

Question 29

What is phase 1 of clinical trials?

Answer 29

Phase I: Testing safety in a small group of healthy volunteers (10 – 100). Safe dosages will be established, and how the body processes the drug (pharmacokinetics) will be monitored. Unblinded = patients and doctors know what the drug is.

Question 30

What is phase 2 of clinical trials?

Answer 30

Small-scale test for efficacy. 50 – 500 patients with the disease will be enrolled. Safety and pharmacokinetics will be monitored. Placebos are used as a comparison. Either single-blind (patient unaware if they are in the test or placebo group) or double-blind (both unaware).

Question 31

What is phase 3 of clinical trials?

Answer 31

Phase III: Large scale test for efficacy, with 500 – 3000 or more patients with the disease over many sites. Stringent comparison to existing treatment. Randomised controlled double-blind trials.

Question 32

What happens after phase 3 of clinical trials?

Answer 32

If Phase III is successful, the company will apply for approval.

Question 33

What happens in phase 4 of clinical trials?

Answer 33

Phase IV: Follow-up studies are conducted post-approval to monitor response in the wider population.