Fragment Based Drug Discovery

Question 1

what is fragment based screening?

Answer 1

REWORD THIS FLASHCARD
related to small molecules drug discovery in the way we know what gene or protein we are targeting.
- start off with much smaller chemicals
- lower affinity and less specific, but are used as a scaffold to then improve affinity and selectivity

• many drugs have common core structures termed scaffolds
• identification of scaffolds that bind a protein of interest allows: (1) growth of that scaffold to increase affinity and specificity, (2) linking of scaffolds to the same ends

Question 2

What makes something a small molecule vs a fragment ?

Question 3

What is the main goal of the fragment-based drug discovery approach?

Question 4

What strategies are used to improve fragment hits?

Question 5

Can you explain the uses of isothermal calorimetry?

Question 6

What are the advantages of FBDD over high-throughput screening approaches ?

Question 7

What makes a good fragment in drug discovery ?

Question 8

How do DSF and SPR compare for screening of fragments

Question 9

What are the rules of 3 and 5 – how do they compare ?

Question 10

What are the applications of xray crystallography in fragment based discovery ?

Question 11

what is fragment merging?

Answer 11

bind 2 different parts of fragment active site, link together to increase affinity

Question 12

what is Lipinski’s rule of 5?

Answer 12

1. MW less than 500 daltons
2. Hydrogen bond donors 5 or <5
3. Hydrogen bond acceptors 10 or <10
4. cLogP (how hydrophobic) 5 or <5

Question 13

what is the rule of 3? What is it for?

Answer 13

developed for fragments, not small molecules.
1. MW less than 300 daltons
2. Hydrogen bond donors 3 or <3
3. Hydrogen bond acceptors 3 or <3
4. cLogP (how hydrophobic) 3 or <3

Question 14

why are rules of 3 and 5 necessary?

Answer 14

so the drugs have the chemical and physical properties to be orally bioavailable.
Not too hydrophobic and not too hydrophilic