Drug Design (IV)

Question 1

Describe the concept of Fragment-Based Drug/Lead design

Answer 1

Start with a small fragment that binds the catalytic site of an enzyme well enough (for its size) then slowly expand and grow it “into” the catalytic pocket with modifications that increase affinity

Question 2

Why are XRD and NMR often used in fragment-based design?

Answer 2

Structure is very important to know where you’re going and what you’re fitting into where, need to be able to determine structure

Question 3

What are the two broad ways to go about FBDD?

Answer 3

Fragment linking: Two different fragments that bind two different parts of the catalytic site are connected together with a linker (that doesn’t affect too much)

Fragment growth: one fragment is grown step by step until it fills up the catalytic site

Question 4

Why is linking 2 fragments a challenge?

Answer 4

You want to find a linker that won’t clash with the protein too much, nor decrease entropy too much

Question 5

What works well as a fragment linker?

Answer 5

Metallo-enzymes(???)

Question 6

How is Ligand Efficiency Calculated? What is a good LE

Answer 6

Free energy of binding/number of heavy (not H) atoms

(this explains why small ligands have low potency but good LE)

Good LE around 0.3-0.35

Question 7

What does the ligand efficiency graph of groups show?

Answer 7

1 dimensional scale

Shows what the -fold increase in LE would have to be to make the addition of the group worthwhile

Can be in terms of size as well as hydrophobicity

Question 8

Why would a drug candidate undergo modifications that decrease affinity?

Answer 8

It’s always worthwhile to sacrifice drug efficiency for a better pharmacokinetic profile