Structure based drug design

Question 1

Describe enzymes as drug targets

Answer 1

Catalyse chemical reactions
HIV-1 protease - target AIDS therapy (cleaves polyprotein precursor to form mature viral proteins)

Question 2

Describe proteases as drug targets

Answer 2

Protease catalyse hydrolysis of amide bonds
Cleave (digest) peptides and proteins
Drug to block process

Question 3

What does structure provide

Answer 3

Active site and position of catalytic residues
Hydrogen bonding interacts with inhibitors
Key ‘conserved’ water molecules
Overall conformation of inhibitor
Surface/shape/volume of active site
Any additional binding site

Question 4

Describe pepstatin

Answer 4

Contains non-natural amino acid statine - position of hydroxyl (-OH) mimics position of amide carbonyl but can’t be hydrolysed
- mechanism for hydrolysis includes ‘transition state’

Question 5

Describe structure to drug of pepstatin

Answer 5

Still subject to degradation via hydrolysis
Needs to be made less peptidic
Selectively - need to avoid inhibiting other proteases - cleavage site between phe-Pro is unique to HIV protease so should avoid other proteases

Question 6

Describe Tipranavir SBDD

Answer 6

Carbonyl oxygen designed to occupy the position of the key conserved water that hydrogen bonds between the flaps and the ligand

Question 7

Why is structure based drug design good

Answer 7

Ability to reduce time as well as cost
3D information - heightening existing and possible new interactions within binding site - used to increase potency and selectivity