Enzymes as Drug Targets - Sweatman

Question 1

Why enzymes as drug targets? Downside?

Answer 1

HIGHLY SPECIFIC, good for drug specificity

Negative: specificity could be limiting; there are families of enzymes & activities

Question 2

What are other potential targets for drugs?

Answer 2

proteins (GPCR), nuclear receptors, DNA

Question 3

Characteristics of enzyme active site

Answer 3

1. Small relative to overall structure
2. 3D = precision
3. Non-covalent: H-bond, electrostatic, hydrophobic, van der Waals
4. excludes bulk solevent

Question 4

What does a pro-drug do? Why?

Answer 4

Uses specific enzyme to transform inactive molecule to active drug in vivo

Why: to limit drug action to specific areas, when structural requirements are of inhibitor are incompatible with oral absorption

Question 5

Describe drug activity in different species

Answer 5

It is specific

Question 6

2 effects of mutation to binding site

Answer 6

1. Can change binding site’s size, flexibility, & chemical interactions
2. Can change affinity for ligands

Question 7

Does a mutation need to occur at the binding site in order to disrupt the ligand binding?

Answer 7

No

Question 8

What are flexible drugs?

Answer 8

Drugs that avoid resistance mutations (ex. NNRTI)

Question 9

Clinical correlate for drug binding affinity

Answer 9

Drug concentration (dose) required to produce a desired effect

Question 10

Receptor agonist

Answer 10

Speeds up binding process

Question 11

Receptor antagonist

Answer 11

Slows down binding process

Question 12

CHART: Two classifications of receptor antagonists

Answer 12

Active site binding antagonists & allosteric antagonists

Question 13

CHART: Describe allosteric binding antagonists

Answer 13

Can be either reversible or irreversible and are all noncompetitive

Question 14

CHART: Describe active-site binding antagonists

Answer 14

Can be reversible (competitive) or irreversible (noncompetitive)

Question 15

CHART: What are the two types of non receptor antagonists?

Answer 15

Chemical antagonists & physiological antagonists

Question 16

DDIs

Answer 16

Drug-drug interactions. Can be responsible for ADEs in elderly & are increasingly important with aging population

Question 17

CYP

Answer 17

Family of enzymes that play a very integral role in clinical agents or drug metabolism.

These enzymes essentially catalyze oxidation of organic substances

Question 18

EM, PM, IM

Answer 18

Extensive metabolizers, poor metabolizers, intermediate metabolizers

Question 19

What do CYP inducers do?

Answer 19

They allow for the isoenzymes of CYP to be expressed. Enzyme induction results from an agents ability to bind to nuclear receptors

Question 20

What can reduced drug metabolism lead to?

Answer 20

Toxicity through the inability of the body to eliminate the drug

Question 21

How does patient drug metabolism play a role in all this?

Answer 21

Optimal activity correlates w patient’s capacity to activate a pro-drug

Question 22

What is tylenol an example of in excess?

Answer 22

Toxicity to hepatic metabolites