Lecture 16

Question 1

Drug

Answer 1

A drug is a chemical substance that causes a change in a biological system. Many drugs exert their effects by interacting REVERSIBLY with very specific biological molecules called receptors.

Question 2

Ligands

Answer 2

Drugs in receptor binding studies.

Question 3

Agonist

Answer 3

A ligand that binds to, and provokes a signal from a receptor via conformational changes in the excited state

Question 4

Antagonist

Answer 4

A ligand that binds to a receptor and induces no signal. Blocks agonist binding. Little conformational change overall. Can result from a ligand with too strong of a bond to its receptor.

Question 5

Receptor

Answer 5

A macromolecular component of the organism that binds the drug and initiates its effect.

Question 6

Induced Fit

Answer 6

• Receptors contain a binding site (hollow or cleft in the receptor surface) that is recognized by the ligand
• Binding of the ligand involves intermolecular bonds
• Binding results in an induced fit of the receptor protein
• Change in receptor shape results in a ‘domino’ effect
• Domino effect is known as Signal Transduction, leading to a chemical signal being received inside the cell
• It departs the receptor unchanged and is not permanently bound

Question 7

Bonds + Induced Fit

Answer 7

• Before the induced fit the intermoleculer bonds are not at optimum length for maximum binding strength
• After induced fit, intermoleculer bond lengths are optimized

Question 8

Balanced Interactions

Answer 8

• Binding needs to be strong enough to hold messenger in place long enough for signal to transduct
• Interaction needs to be weak enough to allow the messenger to depart
• Balance of strong but reversible (usually weak, non-convalent interactions)

Question 9

Drug-Receptor Interactions (2)

Answer 9

1. Irreversible

2. Reversible

Question 10

Irreversible Interactions

Answer 10

• Usually a covalent bond interaction
• Penicillin is an example that acts as a suicide inhibitor
• Sometimes want this interaction like with penicillin or anti-cancer drugs

Question 11

Reversible Interactions

Answer 11

• More desired and drug can be excreted eventually
• Multiple weak interactions that are stable together
• Hydrogen bonds, ionic bonds, hydrophobic bonds

Question 12

Ionic Bonds

Answer 12

• Moderately strong
• Between two opposite charges
• Very common
• Stronger the closer the two charges are (closer the drug is to the receptor)
• Acid bind with bases and bases bind with acids

Question 13

Hydrogen Bonds

Answer 13

• Diplo-diplo interaction between hydrogen and an electronegative atom (O, N, F)
• Differences in electronegativities lead to partial polarizations
• Greater the difference in electronegativities, the greater the bond strength
• Moderately strong, very common
• Weaker than ionic, stronger than hydrophobic

Question 14

Hydrophobic Interactions

Answer 14

• Between nonpolar, organic molecules
• AKA Van der Waals or London forces
• Weak
• Hydrophobes interact with itself over forming hydrogen bonds with water
• From transient dipoles induced by neutral, non-polar molecules

Question 15

Agonist Design

Answer 15

• Agonists mimic the natural messenger of a receptor
• Agonists bind reversibly to the binding site and produce the same induced fit as the natural messenger - receptor is activated
• Similar intermolecular bonds formed as with natural messenger
• Agonists are often similar in structure to the natural messenger

Question 16

Agonist Requirements (3)

Answer 16

1. The agonist must have the correct binding groups
2. The binding groups must be correctly positioned to interact with complementary binding regions
3. The drug must have the correct shape to fit the binding site

Question 17

Correct Binding Groups

Answer 17

• Identify important binding interactions in natural messenger
• Agonists are designed to have functional groups capable of same interactions
• Usually require same number of interactions

Question 18

Correct Positioning of Binding Groups

Answer 18

• Binding groups must be positioned such that they can interact with complementary binding regions at the same time
• One enantiomer of a chiral drug normally binds more effectively than the other
• Different enantiomers likely to have different biological properties

Question 19

Correct Size and Shape

Answer 19

• Agonist must have correct size and shape to fit binding site
• Groups preventing access are called steric shields or steric blocks

Question 20

Design of Antagonists

Answer 20

• Antagonists bind to the binding site but fail to produce the correct induced fit - receptor is not activated
• Normal messenger is blocked from binding
• Antagonists can form binding interactions with binding regions
  in the binding site not used by the natural messenger.
  -Induces a DIFFERENT induced fit from the natural messenger due to its extra interactions