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Rational Drug Design

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Rational Drug Design
Using the 3D Shape of Proteins to
Design Drugs that Inhibit Protein
Function
Before you start this activity, make sure
you have the program Cn3D installed on
your computer.
Download Cn3d from this site
1
Examples of Protein Function
Hormones
Insulin binds to receptors on cell membranes signalling cells
to take up glucose from the blood
Protein Channels
Regulate movement of substances across the
plasma membrane. E.g. The CFTR protein
pumps ions across membranes
Transport
Haemoglobin (far right) in red blood cells
transports oxygen to cells around the body
Source: http://www.biology.arizona.edu/biochemistry/tutorials/chemistry/page2.html
http://www.cbp.pitt.edu/bradbury/projects.htm
2
http://www.abc.net.au/cgi-bin/common/printfriendly.pl?/science/news/enviro/EnviroRepublish_1191825.htm
http://www.umass.edu/microbio/chime/
Catalase - enzyme power!
Hydrogen peroxide, a natural product of metabolism in your
cells, is highly toxic in high concentrations and must be
removed quickly!
Products
Reactants
oxygen
Add ferric ions (Fe 3+)
2
Rate increases 30 000-fold
Hydrogen peroxide
2
water
Add Catalase
Rate increases 100 000 000-fold
Location of active site where
Hydrogen peroxide binds
Source: http://accad.osu.edu/~ibutterf/ibp/molecule/
http://folding.stanford.edu/education/water.htm
3
http://www.opti-balance.com/hyperox.htm
How enzymes do it!
• Enzyme proteins have specific sites where all the action
•
happens. We call this the active site. Molecules that
need to be ripped apart or put together enter the active
site.
Each protein has a specific shape so it will only perform
a specific job.
Joining things together
Ripping things apart
http://chsweb.lr.k12.nj.us/mstanley/outlines/enzymesap/Enzymesap.html
4
http://academic.brooklyn.cuny.edu/biology/bio4fv/page/active_.html
Many toxins are proteins
Ricin from the
seeds of the
castor oil plant
destroys
ribosomes
Funnel web spider
toxin: blocks
movement of
calcium ions.
Source: http://www.wiley.com/legacy/college/boyer/0470003790/cutting_edge/molecular_recognition/molecular_recognition.htm
http://science-univers.qc.ca/image/ricin061.jpg
http://www.staabstudios.com/Spider.htm
5
Protein molecules are polymers
• Proteins are very large polymer molecules. Polymers are made by
linking smaller molecules, monomers, together to make a long
chain.
• In the case of proteins, the monomers are amino acids. There are
20 different amino acids.
AA
AA
AA
AA
AA
AA
AA
6
Why is protein structure important?
• Each protein molecule has a characteristic 3D shape
that results from coiling and folding of the polymer
chain.
•
The function of a protein depends upon the shape of
the molecule.
7
Protein chains
Each protein has a specific sequence of amino
acids that are linked together, forming a
polypeptide
http://www.mywiseowl.com/articles/Image:Protein-primary-structure.png
8
The protein chain folds
Interactions between amino acids in the chain form:
пЃ† alpha helices
пЃ† beta sheets
Together usually form the binding and active
пЃ† Random coils sites of proteins
Source: http://www.rothamsted.bbsrc.ac.uk/notebook/courses/guide/prot.htm#I
9
And folds again!
• After folding, amino
acids that were
distant can become
close
• Now the protein
Source: io.uwinnipeg.ca/~simmons/ cm1503/proteins.htm
chain has a 3D
shape that is
required for it to
function correctly
10
The final protein…
The final protein may be made up of more than one
polypeptide chain.
The polypeptide chains may be the same type or different
types.
Source: http://fig.cox.miami.edu/~cmallery/150/chemistry/hemoglobin.jpg
11
Designing a Drug to Block Amylase
Action
Amylase is a protein that cuts small maltose sugar
molecules off starch molecules.
Another enzyme, maltase, is responsible for breaking
down
STARCHthe maltose molecules into two simple sugars
known as glucose.
Glucose
is absorbed into the blood and transported to
AMYLASE
cells around the body to provide them with energy.
GLUCOSE
MALTOSE
STARCH
GLUCOSE
12
Block the active site of amylase
Active Site
Pig
13
Your turn…
Designing a diet pill
Click on the button on the right to start
exploring amylase with its active site
blocked by a drug.
Amylase in Cn3D
14
Influenza Pandemics
The Spanish Flu in 1918, killed
approximately 50 million people.
It was caused by the H1N1 strain
of influenza A.
The Asian Flu in 1957 was the H2N2
influenza A strain. Worldwide it is
estimated that at least one million
people died from this virus.
The Hong Kong Flu in 1968
evolved into H3N2. 750,000
people died of the virus
worldwide
15
Influenza epidemics
Economic Effects:
•Days away from work
•Providing medical advise and
treatment
•Mortalities
Figure 1. Weekly number of
influenza and pneumonia
deaths per 10 000 000
population in the United States,
France, and Australia (black
line).
16
Designing a Flu Drug
Step 1: looking for protein targets
Influenza viruses are
named according to the
proteins sticking out of
their virus coat.
(H)
There are two types of
protein = N and H.
(N)
N and H have special
shapes to perform
specific jobs for the
virus.
17
Virus
N cuts the links between the viruses
H attaches to cell surface
and the cell surface so virus particles
proteins so virus can enter cell
are free to go and infect more cells.
Proteins on cell surface
Virus genes are released into the
cell.
The lung cell is �tricked’ into using
these genes to make new virus
particles.
Human Lung Cell
18
Your turn…
Explore the research of an Australian team of
scientists headed by Prof Peter Coleman.
They designed the flu drug, Relenza.
Source: http://www.vnn.vn/dataimages/original/images126851_relenza.jpg
http://www.omedon.co.uk/influenza/beans/relenza%20binding.jpg
19
Blocking the active site
RELENZA
Neuraminidase
in Cn3D
This link will open a Cn3D
file of Neuraminidase with
the drug relenza blocking
its active site
20
Venoms to drugs
Link to watch movie
A team of scientists from Melbourne University have patented a toxic
chemical from the venom of an Australian Cone Shell.
The chemical, called ACV1, is an analgesic that will help relieve
chronic pain. It is more powerful than morphine and is not addictive.
This analgesic will be used to treat pain resulting from nerve injury,
post-surgical pain, “phantom limb” pain in amputees, leg ulcers in
diabetics or the pain of terminal AIDS or cancer.
ACV1 treats pain by blocking the transmission of pain along our
peripheral nervous system
This drug could generate an annual profit of greater than1 billion
dollars to the company that develops it!
Source: http://www.unimelb.edu.au/ExtRels/Media/02media/02july08.html
21
Some facts…
пЃ®
Calcium, sodium and potassium ions control essential
functions inside cells: calcium, for example, helps
regulate the contraction of muscle cells.
пЃ®
Ion channels control the entry and exit of ions into and
out of cells.
пЃ®
Some conotoxins act as analgesics, interacting with ion
channel receptors in nerves so the ion channel cannot
open. Blocking ion channels stops ions from entering a
neighbouring nerve fibre. No electrical impulse is set off
so the �pain’ message is switched off! Phew!
22
Sodium ion
Calcium ion
Acetylcholine
The nerve impulse
3. Influx of Calcium
causes acetylcholine to
be released into
synaptic junction.
Synaptic Junction
++
- -
2. Sodium ions accumulate causing
Calcium ion channels to open.
- ++
4. Acetylcholine binds with receptor proteins changing
the shape of the ion channel.
1.
impulse
generated
along axon
5.Electrical
This opens
the sodium
ion channel
to let–insodium
sodium.
ions
(red) rush
and
ions
(green)along
rush the
out
6. Sodium
ionsinset
offPotassium
an electrical
impulse
next nerve cell.
7. The pain message is working.
To block pain we can try to target the ion channels.
23
Acetylcholine at work
Below is an image of a section of a nerve cell cut open
to reveal one of the Sodium Ion channels that studs its
surface. Let’s slice through an ion channel to show its
2 Acetylcholine
inner workings..
molecules bind to
Receptor binding protein
on an ion channel.
Ions move into the neuron
setting off an impulse.
The message is passed on!
The shape of the ion
channel protein changes
so the Na+ gate opens.
Outside Cell
Inside Cell
24
Na+ ion channel
Outside neuronal cell
Cell membrane
(Phospholipid bylayer)
You will explore
this part of the ion
channel.
This is the section
that binds
acetylcholine &/or
drug molecules
causing the ion
channel to change
its shape.
Inside neuronal cell
Some conotoxins block acetylcholine (nACh) receptors that stud the surface of neurons. Let’s
eplore this ion channel in Cn3D
25
Your turn…
Explore the action of a natural Pain
Killer
Follow in the footsteps of
Associate Professor Bruce
Livett and his team to explore
how conotoxins can block
nerve impulses, stopping pain.
Ion Channel with
Neurotransmitter
Ion Channel
with Drug
alpha conotoxin A
Source: http://www.theage.com.au/news/creative--media/painkiller-comes-out-of-its-shell/2005/07/24/1122143728598.html
Alpha conotoxin B
26
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