Lecture 6 (Drug Targets) Flashcards Preview

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Flashcards in Lecture 6 (Drug Targets) Deck (61):
1

To types of drug targets?

1) receptors
2) enzymes

2

What are receptors responsible for?

transmitting a signal to a cell

3

What are enzymes responsible for?

catalyze biochemical reactions

4

List example of receptors

-GPCR's (G-protein couple receptors)
-voltage gated ion channels
-ligand gated ion channels
-nuclear hormone receptors

5

List some different kinds of enzymes

-soluble enzymes
-transmembrane or membrane bound enzymes

6

How do voltage gated ion channels work?

-depolarization causes ion channel to open
-hyper polarization causes ion channel to close

7

How do drugs typically affect a voltage-gate ion channel?

A drug binds to the ion channel and typically inhibits its function

8

T or F: binding can occur on intracellular or extracellular part of the ion channel (voltage gated)

True

9

T of R: binding can not occur on the inside of the pore

False

binding can occur within the pore of the channel itself or on the outside

10

List some examples of binders to voltage gated ion channels

-local anesthetics
-calcium channel blockers
-class 1 and 3 antiarrhythmics

11

How do ligand gated ion channels work?

a ligand binds to the channel and triggers a conformational change which opens the ion channel

12

Where is the receptor binding site normally found for ligand gated ion channels?

on the outside of the membrane

13

Examples of agonists (ligands) that bind to ligand gated ion channels

nicotine
acetylcholine
GABA A
AMPA receptors

14

Explain how nuclear hormone receptors work

-ligand diffuses across cell membrane
-diffuses into nucleus
-binds to nuclear hormone receptor

-then it binds to RE (response element which is some specific sequence of DNA)-this is the promoter of the gene so therefore transcription of the gene will change

**obvs these ligands have to be lipophilic because they have to cross lipid membranes

15

Describe the two parts to nuclear receptors:

DBD (DNA binding domain) - binds to DNA
LBD (ligand binding domain) - binds to nuclear hormone (ligand)

16

Receptor for estradiol

estrogen receptor (ER)

17

receptor for testosterone

androgen receptor

18

receptor for progesterone

progesterone receptor

19

receptor for cortisol

glucocorticoid receptor

Other receptor:
mineralocorticoid receptor

20

receptor for aldosterone

mineralocorticoid receptor

Other receptor:
glucocorticoid receptor (weak)

21

receptor for Vitamin A

retinoic acid receptor

22

receptor for Vitamin D

vitamin D receptor

23

thyroid hormone

thyroid hormone (T3, T4) receptor

24

Describe transmembrane enzymes

-these are a group of receptors that have an extracellular ligand binding domain and an intracellular enzymatic domain within the same protein.

25

examples of transmembrane enzymes ?

-EGF (epidermal growth factor)
-insulin receptors which contain intrinsic tyrosine kinases in the cytoplasmic domain

26

What does tyrosine kinase do?

adds phosphate to tyrosine

27

What does EGFR do?

it's a transmembrane receptor tyrosine kinases which is needed for the growth and differentiation of epithelial cells.

over expression of EGFR is found in epithelial cancers.

28

What can phosphotyrosine bind to?

proteins with an SH2 doamins

29

What does RAS activate?

RAS activates a protein kinase cascade called the mitogen-activated protein kinase pathway (MAPK)

30

What does the kinase result in?

it results in phosphorylation of a number of transcription factors in the nucleus, including the cAMP response element-binding protein (CREB)

*see slide 14

31

For enzymes the equivalent of an antagonist is an ____

inhibitor

32

The equivalent of an agonist would be another ____

substrate
**although this is almost never the goal of drug discovery

33

______ help catalyze rxns from substrate to product

enzymes

34

What does GPCR stand for?

G-protein coupled receptor

35

Describe GPCRs

-probably the most important group of receptors
-target for about 45% of drugs on the market

36

What are the 3 components of GPCRs?

-receptor on outside of membrane binds ligand

-G-protein on inside of membrane senses signal from ligand-receptor interaction

-effector protein - binds G-protein and produces or inhibits production of a second messenger

37

Describe the structure of a GPCR

-large protein that spans the membrane
-7 alpha helices that cross membrane = 7 transmembrane helix receptors
-ligand binding on extracellular sie
-g-protein (signalling protein) is on intracellular side

38

What can the G-protein bind?

GDP
GTP

39

What 3 subunits does a G-protein have?

alpha
beta
gamma

40

understand slide 18

okay

41

G alpha s (stimulatory)

it activates AC (adenylate cyclase) and opens calcium channels leading out of the cell

42

G alpha s (stimulatory)
second messenger?

cAMP produced

43

G alpha i (inhibitory)

inhibits AC (adenylate cyclase) and opens K+ channels

44

G alpha i (inhibitory)
second messenger?

cAMP inhibited

45

Go

activates receptors that inhibit calcium ion channels leading out of the cell

*inhibit calcium ion channels

46

G alpha q

actives PLC B (phospholipase C beta)

47

G alpha q
second messenger?

DAG and IP3 produced

48

look at slide 20

okay

49

adenylate cyclase (AC) produces what?

Ppi and cAMP

50

The active site of AC is blocked until ?

G alpha s binds (which allows ATP to enter)

51

What are some effects of AC activity

increased glucose
decreased glycogen synthesis
increased lipolysis

*slide 22

(all through phosphorylation)

52

Describe G alpha i

-cAMP production is being inhibited.
-therefore PKA remains inactive

*then the beta gamma subunits also opens a K+ channel which results in hyper polarization of membrane (K can leave the cell)

53

Describe G alpha q

membrane bound PLC B binds G alpha q and PLC B is activated

PLC B hydrolyzes phosphatidylinositol diphosphate (PIP2) to second messengers diacylglycerol (DAG) and inositol triphosphate (IP3)

*PLC B activated
which turns
PIP2 into
DAG and IP3

54

____ is bound to the membrane

PLC B

55

___ is a phospholipid found in membrane

PIP2

56

___ being hydrophobic stays in the membrane

DAG

57

___ is a hydrophilic molecule and stays in cytosol

IP3

58

Gaq results in an increase in ?

intracellular calcium

59

What does the calcium produced do?

calcium also binds to calmodulin (CaMCa) and stimulates PDE which hydrolyzes cAMP to 5'AMP

*this counteracts the signal from G alpha s

see slide 26 for diagram

60

AC and G alpha s ___ intracellular calcium

decrease!!!

61

What does the decrease in intracellular calcium do?

it counteracts the effects of G alpha q