EXAM 3 - Principles of Biological Assays & Lead Compound Identification

Question 1

Define IC50.

Answer 1

The concentration of drug at which 50% of the target is inhibited.

Question 2

What does a high IC50 (10) mean versus a low IC50 (2)?

Answer 2

10 –> higher IC50 = less active drug
2 –> lower IC50 = more active drug
* IC50 = 2 –> means that this drug needs less concentration to have the same effect as IC50 = 10.
* IC50 = 2 binds better between the target and the compound

Question 3

List the steps to generate IC50 value.

Answer 3

1. Test 8-10 different concentrations of drug for biological activity.
2. Measure biological activity and convert to a % value
3. Plot % activity as a function of concentration
   * % activity (y-axis) vs. log [drug] (x-axis)

Question 4

What is a lead compound?

Answer 4

The inital small molecule that has promising biological activity against your target of interest
* has ideal structure –> ability to modulate target

Question 5

Explain the difference between the lead compound sources.

Answer 5

• Natural products
• Synthetic products
• Existing drugs (‘Me too’ drugs)
• Natural ligands

Question 6

Describe natural product lead compounds.

Answer 6

Natural products - usually comes from natural products or animals (symbiotic)

Question 7

Describe synthetic product lead compounds.

Answer 7

Synthetic products - made synthetically in a lab using High-Throughput Screening (HTS)

Question 8

Describe existing drug lead compounds.

Answer 8

Existing drugs (‘Me too’ drugs) - uses a preexisting structure of a patent drug
* it uses very similar structure but changes the slightest thing to make the molecule structure different enough to work the same but be considered a different drug (repurposing)

Question 9

Describe natural ligand lead compounds.

Answer 9

Natural ligands - binds to and interacts with target as natural ligand look-alike
* this works because the endogenous ligand is known to interact with the receptor.

Question 10

How does high-throughput screening work?

Answer 10

Thousands to millions of small compounds thrown into target to see which one interacts with the target
* you can see which works well and analyze to find promising structures

Question 11

What is the rult of three for lead compounds?

Answer 11

Small molecules in a library should have the following properties:
* MW < 350 g/mol
* LogP of ~3
(these values are lower than lipinski’s rule values bc when you modify/optimize a drug/compound –> the MW and LogP will increase)