Download Receptor/enzymes

Receptor/enzymes
Drug Design
• Most drugs work on proteins
• Somehow interfere with a biochemical
process
– Can shut down
– Can activate
Proteins
• Polymers of amino acids that have some
function
– Enzymes
– Receptors
Protein structure
•
•
•
•
•
•
Function very dependant on structure
Polymers of amino acids
Huge molecules
Fold back on selves
Held together by weak interactions
Disruption of structure called denaturation
Hemoglobin structure example
Enzymes
• Biological catalysts
• Speed up reactions without being consumed
O
O
NADH
NAD+
O
O
OH
O
CH3
lactate dehydrogenase
CH3
lactate
pyruvate
Enzymes often involved in
metabolic pathways
acetyl CoA
O
O
O
acyl-CoA
R
CH 2
CH 2
CH 2
C
S-CoA
R
CH 2
C
CH 3
S-CoA
C
S-CoA
FAD
Acyl-CoA Dehydrogenase
FADH 2
HSCoA
thiolase
O
beta-enoyl CoA
O
O
R
CH
CH
CH2
C
S-CoA
R
CH 2
C
CH 2
beta-ketoacyl CoA
H2O
enoyl-CoA hydratase
beta-hydroxyacyl-CoA
dehydrogenase
NADH
NAD+
OH
R
CH 2
CH
O
CH 2
C
S-CoA
beta-hydroxyacyl CoA
C
S-CoA
Enzyme mechanism
• E + S > ES > EP > E + P
Receptors
• Molecules on a cell surface
• Binding by “ligand” on outside of cell
causes changes on the inside of the cell
– Molecule brought in
– Cellular signalling
Receptor binding causes change
on inside of cell
Drugs
• Most drugs work on receptors or enzymes
• Problems
– Receptor/enzyme works too well
– Receptor/enzyme doesn’t work well enough
Lock and Key Hypothesis
• Protein and ligand
have complementary
shapes.
• Interactions must also
be complementary
– If enzyme charge is
negative, substrate
must be positive
– If pocket is nonpolar,
ligand must be
nonpolar
Competitive binding
I
E
S
I
E
S
• Drug (I) binds instead of substrate/ligand
Drug binds instead of substrate
• Antagonists
– Binding prevents substrate binding
• Blocks response
• Agonists
– Binding of drug instead of substrate elicits
response
• turns switch on
Drugs can bind to other sites
• “allo” binding
– Can activate
– Can deactivate
– Can attenuate
Inhibition at allo site
S
I
I
Inhibitor binds to an allosteric site on the enzyme
Changes active site so substrate doesn’t bind
Allosteric Activation
S
S
A
A
• Active site will not bind substrate
• Allosteric activator binds and changes shape of
active site
• Now substrate binds
Antibiotics
• Bacteria different than human cells
– Similar biochemistry
Penicillin prevents formation of
bacterial cell walls
Viruses
• Contains DNA surrounded by protective shell or
capsid
• Uses host cells enzymes and ribosomes for
replication
• Lysogenic phase: viruses may remain dormant
inside host cells for long periods. There is no
obvious change in their host cells
• Can enter the lytic phase: new viruses are
produced, assemble, and burst out of the host
cell.
• The cell is killed and other cells are infected
Typical Viral structure
Lytic and lysogenic life cycles
Antivirals
• Interfere with some aspect of life cycle
– Some with attachment
– Some with self assembly
– etc