Hardcastle content

Question 1

What are affinity labels

Answer 1

Possess a reactive functional groups that forms a covalent bond with the protein

Question 2

Give an example of an affinity label

Answer 2

Aspirin is an affinity labels, for cyclooxygenase. Aspirin binds to active site of cyclooxygenase and irreversibly acylates ser-530

Question 3

Describe the IC50 for affinity labels

Answer 3

IC50 is time dependent, compounds will appear more potent the longer there are incubated with the enzyme. Potency not dependent on substrate concentration

Question 4

What are mechanism-based inhibitors

Answer 4

Structurally very similar to the substrate

Question 5

What are the 3 steps for inhibition for mechanism based inhibitors

Answer 5

1) competition for substrate binding site
2) reaction with the catalytic site of the enzyme- forms a reactive species
3) reactive species forms a covalent bond with the enzyme
Drug structure is altered upon binding

Question 6

Give an example of mechanism based inhibitors

Answer 6

Tranylcypromine mechanism based inhibitor of monoamine oxidises (MAOs)

Question 7

What does SAR stand for

Answer 7

Structure activity relationship

Question 8

What does SPR stand for

Answer 8

Structure-property relationship

Question 9

What does QSAR stand for

Answer 9

Quantitive structure-activity relationships

Question 10

What do we mean by structure activity relationship

Answer 10

How biological activity relates to chemical structure.
Biological activity relates to IC50 and KI

Question 11

What do we mean by structure-property relationship

Answer 11

Physicochemical properties (e.g pKa, LogP, solubility)

Question 12

What do we mean by quantitive structure-activity relationships

Answer 12

Relate a biological activity to some numerical property for a series of compounds, derive a numerical value for a given structural element

Question 13

What is the Hammett relationship

Answer 13

Is a linear feee energy relationship between Ka and K for substituent X

Question 14

What is the Hammett equation

Answer 14

Log k/k0 = pσ

Question 15

What is σ in the Hammett equation

Answer 15

The electronic parameter
σx = pKa (benzoic acid) - pKa (substituted benzoic acid)

Question 16

What does a negative σ mean

Answer 16

Electron donating group

Question 17

What does positive σ mean

Answer 17

Electron withdrawing group

Question 18

What does p mean in the Hammett equation

Answer 18

The reaction parameter p is unique for a particular system. A measure of how sensitive the system is to the parameter σx

Question 19

What is the Hansch relationship

Answer 19

Linear free-energy relationship between lipophilicity and biological activity for substituent X

Question 20

What is the Hansch equation

Answer 20

πx = logPx - LogPH

Question 21

If π x is negative then X is …

Answer 21

Polar

Question 22

If πx is positive the X is …

Answer 22

Lipophilic

Question 23

What is the Craig plot

Answer 23

2D plot of parameters for common substituents
E.g a plot where x= π and y= σ

Question 24

Using a Craig plot how would you explore the SAR for σ and pi

Answer 24

Select different substituent from each quadrant

Question 25

Using a Craig plot how would you explore established SAR

Answer 25

Select substituents close to the most potent ones already known

Question 26

What property’s must a good drug need to optimise and what does these mean

Answer 26

potency - does it hit the target? solubility - will it dissolve in stomach Bioavailability - will it get into the patient? Stability - how long will it survive in the body? Toxicity - will or have unwanted side-effects?

Question 27

What conditions is high blood cholesterol levels linked to

Answer 27

Angina Heart attack Stroke Cardiovascular diseases

Question 28

How is cholesterol synthesised

Answer 28

Squalene is converted to squalene epoxide by squalene monooxygenase. Squalene epoxide is then converted to lanosterol using squalene epoxidase. The lanosterol is converted into cholesterol through a series of enzymatic reactions

Question 29

Describe how we lower cholesterol levels

Answer 29

HMG-CoA reductase inhibitors or statins lower cholesterol by competitively inhibiting the enzyme HMG-CoA which is used in cholesterol synthesis in the liver

Question 30

Describe the mechanism of action for HMG-CoA reductase inhibitors

Answer 30

Dihydroxy acid groups bind to polar HMG binding site, statins exploit the conformational flexibility of HMGR to create a hydrophobic binding pocket near the active site