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Med Chem > Lecture 6 (Drug Targets) > Flashcards

Lecture 6 (Drug Targets) Flashcards

1
Q

To types of drug targets?

A

1) receptors

2) enzymes

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2
Q

What are receptors responsible for?

A

transmitting a signal to a cell

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3
Q

What are enzymes responsible for?

A

catalyze biochemical reactions

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4
Q

List example of receptors

A
  • GPCR’s (G-protein couple receptors)
  • voltage gated ion channels
  • ligand gated ion channels
  • nuclear hormone receptors
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5
Q

List some different kinds of enzymes

A
  • soluble enzymes

- transmembrane or membrane bound enzymes

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6
Q

How do voltage gated ion channels work?

A
  • depolarization causes ion channel to open

- hyper polarization causes ion channel to close

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7
Q

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

A

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

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8
Q

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

A

True

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9
Q

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

A

False

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

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10
Q

List some examples of binders to voltage gated ion channels

A
  • local anesthetics
  • calcium channel blockers
  • class 1 and 3 antiarrhythmics
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11
Q

How do ligand gated ion channels work?

A

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

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12
Q

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

A

on the outside of the membrane

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13
Q

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

A

nicotine
acetylcholine
GABA A
AMPA receptors

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14
Q

Explain how nuclear hormone receptors work

A
  • 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

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15
Q

Describe the two parts to nuclear receptors:

A

DBD (DNA binding domain) - binds to DNA

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

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16
Q

Receptor for estradiol

A

estrogen receptor (ER)

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17
Q

receptor for testosterone

A

androgen receptor

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18
Q

receptor for progesterone

A

progesterone receptor

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19
Q

receptor for cortisol

A

glucocorticoid receptor

Other receptor:
mineralocorticoid receptor

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20
Q

receptor for aldosterone

A

mineralocorticoid receptor

Other receptor:
glucocorticoid receptor (weak)
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21
Q

receptor for Vitamin A

A

retinoic acid receptor

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22
Q

receptor for Vitamin D

A

vitamin D receptor

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23
Q

thyroid hormone

A

thyroid hormone (T3, T4) receptor

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24
Q

Describe transmembrane enzymes

A

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

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25
Q

examples of transmembrane enzymes ?

A
  • EGF (epidermal growth factor)

- insulin receptors which contain intrinsic tyrosine kinases in the cytoplasmic domain

26
Q

What does tyrosine kinase do?

A

adds phosphate to tyrosine

27
Q

What does EGFR do?

A

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
Q

What can phosphotyrosine bind to?

A

proteins with an SH2 doamins

29
Q

What does RAS activate?

A

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

30
Q

What does the kinase result in?

A

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
Q

For enzymes the equivalent of an antagonist is an ____

A

inhibitor

32
Q

The equivalent of an agonist would be another ____

A

substrate

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

33
Q

______ help catalyze rxns from substrate to product

A

enzymes

34
Q

What does GPCR stand for?

A

G-protein coupled receptor

35
Q

Describe GPCRs

A
  • probably the most important group of receptors

- target for about 45% of drugs on the market

36
Q

What are the 3 components of GPCRs?

A
  • 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
Q

Describe the structure of a GPCR

A
  • 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
Q

What can the G-protein bind?

A

GDP

GTP

39
Q

What 3 subunits does a G-protein have?

A

alpha
beta
gamma

40
Q

understand slide 18

A

okay

41
Q

G alpha s (stimulatory)

A

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

42
Q

G alpha s (stimulatory)

second messenger?

A

cAMP produced

43
Q

G alpha i (inhibitory)

A

inhibits AC (adenylate cyclase) and opens K+ channels

44
Q

G alpha i (inhibitory)

second messenger?

A

cAMP inhibited

45
Q

Go

A

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

*inhibit calcium ion channels

46
Q

G alpha q

A

actives PLC B (phospholipase C beta)

47
Q

G alpha q

second messenger?

A

DAG and IP3 produced

48
Q

look at slide 20

A

okay

49
Q

adenylate cyclase (AC) produces what?

A

Ppi and cAMP

50
Q

The active site of AC is blocked until ?

A

G alpha s binds (which allows ATP to enter)

51
Q

What are some effects of AC activity

A

increased glucose
decreased glycogen synthesis
increased lipolysis

*slide 22

(all through phosphorylation)

52
Q

Describe G alpha i

A
  • 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
Q

Describe G alpha q

A

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
Q

____ is bound to the membrane

A

PLC B

55
Q

___ is a phospholipid found in membrane

A

PIP2

56
Q

___ being hydrophobic stays in the membrane

A

DAG

57
Q

___ is a hydrophilic molecule and stays in cytosol

A

IP3

58
Q

Gaq results in an increase in ?

A

intracellular calcium

59
Q

What does the calcium produced do?

A

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
Q

AC and G alpha s ___ intracellular calcium

A

decrease!!!

61
Q

What does the decrease in intracellular calcium do?

A

it counteracts the effects of G alpha q

Med Chem (11 decks)

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