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

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

• 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