Theme 3 Lecture 11

Question 1

What are legacy (previous) libraries and their role in drug discovery? (Uses HTS)

Answer 1

Contain compounds from previous drug discovery campaigns.
These are also known as diversity libraries, they usually have a low success (1 in 10,000) compounds are successful.

Question 2

What is the difference between diversity and targeted compound libraries?

Answer 2

Diversity libraries are a random set of compounds with good drug or lead like properties with no specific biological target

Targeted libraries have compounds that are designed to have biological activity at the specific target.

Question 3

What is the general concept of Lipinski’s Rule of Five?

Answer 3

Evaulates drug-likeness of a compound based on physicochemical properties.

Question 4

What are the criterias for lipinski’s rules

Answer 4

<5 hbonds
Mw <500
LogP(octanol-water partition coefficient) <5
<10 HBA

Question 5

How are drug-like properties defined?

Answer 5

Have acceptable ADME and tox properties which survives phase 1 human trials.

Question 6

What are lead-like properties?

Answer 6

Suitable starting point for drug discovery, free of major liabilities.

Question 7

How do medicinal chemists influence drug-like and lead-like properties?(polar and nonpolar groups)

Answer 7

Modifying chemical structure of the compound to e.g Non-polar groups for increase lipophilic pockets and polar groups added for increased h bonding

Question 8

For oral compounds what is suggested?(bioavailability)

Answer 8

To work close to lipinski’s rule of 5 for good oral bioavailability

Question 9

Diversity Library issues?

Answer 9

HTS to start which is usually high Mw, poor ADME and poor efficacy and affinity

Question 10

What is the significance of the HIV protease in drug discovery? (using previous knowledge)=renin

Answer 10

Using knowledge from projects on other aspartyl proteases like renin. This approach led to the development of effective HIV protease inhibitors

Question 11

How were inhibitors against HIV protease developed? “dog renin”

Answer 11

Screening compounds for renin inhibition.
Synthetic peptides “dog renin” were found to inhibit HIV protease.

Question 12

What is the history of the anti-epileptic drug Topiramate?

Answer 12

Was initially a synthetic intermediate
It demonstrated anticonvulsant activity in a phenotypic screen for seizures.