receptor/enzymes. drug design most drugs work on proteins somehow interfere with a biochemical...
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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
CH3
O O
CH3
O O
OH
lactatepyruvate
NAD+NADH
lactate dehydrogenase
Enzymes often involved in metabolic pathways
CH2R CH2 CH2 C
O
S-CoA
FAD
FADH2
CHR CH CH2 C
O
S-CoA
Acyl-CoA Dehydrogenase
acyl-CoA
beta-enoyl CoA
OH2
enoyl-CoA hydratase
CH2R CH CH2 C
O
S-CoA
OH
beta-hydroxyacyl CoA
NAD+
NADHbeta-hydroxyacyl-CoA
dehydrogenase
CH2R C CH2 C
O
S-CoA
O
thiolaseHSCoA
CH3 C
O
S-CoA
beta-ketoacyl CoA
acetyl CoA
CH2 C
O
S-CoAR
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
• Drug (I) binds instead of substrate/ligand
E S
I
EI
S
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 enzymeChanges active site so substrate doesn’t bind
Allosteric Activation
• Active site will not bind substrate• Allosteric activator binds and changes shape of
active site• Now substrate binds
S
A
A
S
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