Drug Design

Question 1

What is the key role the neuraminidase enzyme plays for influenza?
Why is it important for us to know?

Answer 1

Without this enzyme, new viruses are no longer able to bud from the host cells.

Question 2

Single subunit of influenza virus looks like:

Answer 2

Note, there are 4 of these in the whole enzyme.
6-bladed propeller.

Question 3

Why is this sugar important?

Answer 3

A very common neruaminic acid.
Important because this is one of the VERY common sugars on human cell surfaces that neuraminidase (influenza virus enzyme) cleaves to gain access into host.

Question 4

What is the proposed reaction for neuraminidase catalyzed glycoside hydrolysis reaction.

Answer 4

Orange square is where Neruaminidase stabilizes reaction.

Question 5

What do you need to know about DANA?

Answer 5

A transition state analog neruaminidase inhibitor.
Pros: would inhibit neruaminidase
Cons: poor affinity (requires high concentration of drug), also affects human neuraminidase.
Note: planarity!

Question 6

Scientists changed DANA to take out the partially negative charged hydroxyl group because it was next to Glu (neg. Amino acid) and replace it with a positively charged side group.

Answer 6

It helped significantly!
Remember for Ki: smaller values = stronger inhibition.
So strengthen binding for Flu Neruaminidase and weaken binding to human neuraminidase.

Question 7

For orally available medicines a fine balances required. What are the two things that it needs to balance?

Answer 7