Rational Drug Design

Question 1

What is rational drug design?

Answer 1

Designing a drug based upon knowledge of the target molecule(s) structure and cellular expression

Question 2

What form cna the drug be in rational drug design

Answer 2

Small chemical
Peptide
RNA
Biologic macromolecule

Question 3

What is the problem with peptides binding intracellular?

Answer 3

Have to work out how to get your molecule into a cell before it has its affects

Question 4

What is the drug market passed on types of drugs currently?

Answer 4

Mostly small molecule drugs
Then biologics
Then peptides - making up just 5%

Question 5

How many peptides bind intracellular v extracellular?

Answer 5

<15% bind intracellular targets, most are extracellular

Question 6

What are small molecule chemical libraries good?

Answer 6

Any large companies will have a bank of chemicals which have been synthesised
Know what chemical is in what well and plate and these will be stored in a bank
Know a lot about things you might want to target etc.

Question 7

What is the first approach to target structure based?

Answer 7

Binding site identification
Identify compounds that fit
Lead compound generation
Search known DB of compounds for that fit
Viral screening/docking

Question 8

What is approach 2 of ligand structure-based

Answer 8

Known ligand(s)
Identify compounds similar to ligand
Select those with appropriate binding
Develop new compounds

Less requirement to know the structure of the target

Question 9

What is good about caspase and inflammasome inhibitors?

Answer 9

Start making drugs that inhibit things like the inflammasome
Somebody makes the drug for one particular disease but inflammasomes are relevant in so many diseases so can try it for a different disease

Question 10

What are combinatorial technologies

Answer 10

The synthesis of simple chemical building blocks into complex strutcure on a large scale

Question 11

What is molecular mimicry?

Answer 11

Having an antibody that binds really well, go looking for a peptide that would bind into the same binding site that the polysaccharide would, as long as it is right shape and charge

Question 12

What is the example of using adeno associated virus in rational drug design?

Answer 12

Made a library and injected into mice
Wild type adenovirus didn’t bind well but one with change made to surface had a much higher binding affinity, this is pseudotyping

Question 13

What are the aims of biologic macromolecules?

Answer 13

Engaging immune cells
Local concentration enrichment
Matchmaking
Drug delivery

Question 14

What are similarities between biologic macromolecules and small molecule drug-design?

Answer 14

Pre-defined target molecule and cell types
Requirement to modify the cells behaviour/interactions

Question 15

What approaches are different for small molecules and biologic macromolecules?

Answer 15

Obtain binders for each target molecule
Engineer to combine the properties of each relevant molecule
Solve problems to ensure correct assembly and function

Question 16

What are aptamers?

Answer 16

Scaffold molecules that can be used to deliver things to cells to hep them bind - they are largely nucleic acids

Question 17

What are available drugs from combinatorial approchaes?

Answer 17

Ribosome display
- cetuximab
- natalizumab
Aptamers
- pegaptanib

Question 18

What can tetherbodies be used for?

Answer 18

Trasnfer things through blood brain barrier for example, across hard to breach surfaces

Question 19

What is sweeping antibody matchmaker?

Answer 19

Have an antibody that binds to a receptor on a cell, this antibody also binds to a target molecule that you want to remove from the environment
So if you ensign this carefully, cna have antibody recycled up to surface but can start to remove that target molecule from the environment, because your recycling it into a cell and sending it off for degradation