Structure Activity Relationships (Drug Discovery 3)

Question 1

What are SARs?

Answer 1

Structure activity relationships
- They are studied to help optimise on-target activity and sometimes to minimise off-target toxicity
- Identifies the parts of the molecule that are important for biological activity

Question 2

What do SARs form?

Answer 2

Analogues containing the pharmacophores are designed, synthesised and evaluated

Question 3

How do drugs bind to target proteins?

Answer 3

• Most drugs bind through non-covalent interactions (not including full bonds between atoms)
  5 main non-covalent interactions:
• Hydrogen bonding
• Ionic interactions
• Van der Waals attractions
• Hydrophobic interactions
• pie-Stacking

Question 4

What is hydrogen bonding?

Answer 4

• Weak covalent-like bonding between an electronegative atom (F, N, O) and a nearby hydrogen
• Approx 1-10% of the strength of a covalent bond

Question 5

What are ionic interactions?

Answer 5

• Electrostatic attractions between ions of different charges
• Approx 5-25% of the strength of a covalent bond
• No electron sharing is involved

Question 6

What is Van Der Waals attractions?

Answer 6

• All atoms and bonds are attracted to each other
• Localised temporary dipoles
• Very weak individual forces
• Many van der Waals interactions add up to good binding, if a drug fits its binding site snugly

Question 7

What are hydrophobic interactions?

Answer 7

• Hydrophobic (non-polar) parts of the molecules don’t like to interact with water
• If a hydrophobic drug is not inside a hydrophobic pocket in the binding site, then both binding site and the drug molecule have to interact with water
• Binding free energy comes from entropy

Question 8

What is pie-stacking?

Answer 8

• Face-to-face (attraction)
• Edge-to-face (weak attraction)
• Edge-to-edge (repulsion)

Question 9

A few drugs bind covalently, what is an example?

Answer 9

Ethacrynic acid
- Is a diuretic which acts by blocking reabsorption of sodium ions

Question 10

What is required for SAR in antibacterial drugs (penicillins)

Answer 10

• Strained beta-lactam ring is important
• Carboxylate is essential
• Bicyclic ring system in important
• Acrylamino side-chain is important
• Sulfur is usual but not essential
• Cis Stereochemical configuration is important in the beta-lactam