Lecture 6 (Drug Targets) Flashcards by Sam Myers

To types of drug targets?

1) receptors

2) enzymes

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What are receptors responsible for?

transmitting a signal to a cell

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What are enzymes responsible for?

catalyze biochemical reactions

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List example of receptors

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

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List some different kinds of enzymes

soluble enzymes

- transmembrane or membrane bound enzymes

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How do voltage gated ion channels work?

depolarization causes ion channel to open

- hyper polarization causes ion channel to close

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

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

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

True

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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

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List some examples of binders to voltage gated ion channels

local anesthetics
calcium channel blockers
class 1 and 3 antiarrhythmics

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How do ligand gated ion channels work?

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

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

on the outside of the membrane

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

nicotine
acetylcholine
GABA A
AMPA receptors

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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

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Describe the two parts to nuclear receptors:

DBD (DNA binding domain) - binds to DNA

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

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Receptor for estradiol

estrogen receptor (ER)

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receptor for testosterone

androgen receptor

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receptor for progesterone

progesterone receptor

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receptor for cortisol

glucocorticoid receptor

Other receptor:
mineralocorticoid receptor

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receptor for aldosterone

mineralocorticoid receptor

Other receptor:
glucocorticoid receptor (weak)

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receptor for Vitamin A

retinoic acid receptor

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receptor for Vitamin D

vitamin D receptor

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thyroid hormone

thyroid hormone (T3, T4) receptor

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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.

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examples of transmembrane enzymes ?

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

What does tyrosine kinase do?

adds phosphate to tyrosine

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.

What can phosphotyrosine bind to?

proteins with an SH2 doamins

What does RAS activate?

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

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

For enzymes the equivalent of an antagonist is an ____

inhibitor

The equivalent of an agonist would be another ____

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

______ help catalyze rxns from substrate to product

enzymes

What does GPCR stand for?

G-protein coupled receptor

Describe GPCRs

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

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

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

What can the G-protein bind?

GDP | GTP

What 3 subunits does a G-protein have?

alpha beta gamma

understand slide 18

okay

G alpha s (stimulatory)

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

G alpha s (stimulatory) | second messenger?

cAMP produced

G alpha i (inhibitory)

inhibits AC (adenylate cyclase) and opens K+ channels

G alpha i (inhibitory) | second messenger?

cAMP inhibited

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

G alpha q

actives PLC B (phospholipase C beta)

G alpha q | second messenger?

DAG and IP3 produced

look at slide 20

okay

adenylate cyclase (AC) produces what?

Ppi and cAMP

The active site of AC is blocked until ?

G alpha s binds (which allows ATP to enter)

What are some effects of AC activity

increased glucose decreased glycogen synthesis increased lipolysis *slide 22 (all through phosphorylation)

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)

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

____ is bound to the membrane

PLC B

___ is a phospholipid found in membrane

PIP2

___ being hydrophobic stays in the membrane

DAG

___ is a hydrophilic molecule and stays in cytosol

IP3

Gaq results in an increase in ?

intracellular calcium

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

AC and G alpha s ___ intracellular calcium

decrease!!!

What does the decrease in intracellular calcium do?

it counteracts the effects of G alpha q