Week 6 Readings

Question 1

What does potency mean?

Answer 1

How strongly a drug interacts with its target

How little drug is required to have the desired effect (like golf - the lower the score the better)

Question 2

What improves the potency of a drug?

Answer 2

poor match with target = poor potency

Better match with target = good potency

more/ better binding interactions between drug and target = improving potency

Question 3

What happens if a drug has a good potency against its target?

Answer 3

• the less likely it is to hit other targets (toxicity)
• the less you need to dissolve (solubility)
• the less you need to be absorbed (permeability)

Question 4

What can happen if you improve the potency of a drug?

Answer 4

the side effects are also caused at a lower concentration

Question 5

What is the pharmacophore of a compound?

Answer 5

the part of the structure that binds to the target

Question 6

How can we figure out how and why a compound works?

Answer 6

take the compound and remove or modify each group

loss of activity = essential
no change in activity = not essential

Question 7

What does the extension of a compound structure do for its potency?

Answer 7

increases potency and finds additional binding interactions

Question 8

What does the extension of a compound structure do for its selectivity?

Answer 8

increases selectivity

Question 9

What does rigidification to do potency and selectivity?

Answer 9

increases both by preventing the structure from flopping out of conformation

Question 10

What is osteoporosis?

Answer 10

disease when bones become weak, prone to break or collapse

Question 11

What were osteoclasts?

Answer 11

inhibit bone formation (remove bone)

Question 12

What were osteoblasts?

Answer 12

activate bone growth (build bone)

Question 13

How was phenotypic screening done for osteoporosis?

Answer 13

osteoclasts were placed in a plate to grow, and drugs were added to see if it would kill them, but drugs were also targeted against osteoblasts to make sure they’d survive

Question 14

What is a good potency for approved drugs?

Answer 14

20 nM

Question 15

What was the potency found for the osteoporosis drug?

Answer 15

3nM

Question 16

What was done to the drug to improve potency?

Answer 16

F group was added on, which killed all cells

Question 17

When needing a new drug, how do we find a starting point?

Answer 17

• high-throughput screening
• fragment screening
• in silico screening

Question 18

Where do we look for chemicals for new drugs?

Answer 18

compound libraries
a massive collection of compounds (500 000 - 2 million)

Question 19

What is considered a “hit”?

Answer 19

the rare chemical that gives a positive response in a high-throughput screen

Question 20

What is target-based screening?

Answer 20

known target looking for chemicals that modulate target or pathway

Question 21

What is phenotypic screening?

Answer 21

only looking for the desired effect (killing certain cells)
Find an active compound then consider how it works

Question 22

What is in silico screening?

Answer 22

experiments on the computer

Question 23

What is fragment screening?

Answer 23

the library of fragments is screened in vitro using different techniques to detect binding to a target

Question 24

What is ADME(T)

Answer 24

pharmacokinetics
- absorption
- distribution
-metabolism
- excretion
- toxicology

Question 25

If we start with 50 nM of a drug to treat a disease, is that all we need to worry about?

Answer 25

Drug levels fall between doses (stay above 50nM)… now at 100nM

Blood has proteins which will bind to to drug, therefore we need to swallow 1000 nM to get 100nM to the target

Question 26

What does the solubility of a drug depend on?

Answer 26

the potency of a drug
High potency: lower solubility is okay
Poor potency: higher solubility (more needs to dissolve)

Question 27

Why does permeability cause a problem?

Answer 27

if the drug can’t pass through the gut wall to reach circulation, it will pass straight through and be excreted

Question 28

How is permeability measured in vitro?

Answer 28

permeability assays measure the rate at which a compound passes through a layer of cell

Question 29

How good does the permeability need to be?

Answer 29

96% of drugs act in the brain, they have to have permeability of >150 nm/sec

Question 30

What is the efflux ratio?

Answer 30

the permeability out/ permeability in