IC8 - SAR Modification

Question 1

What is homologation?

Answer 1

Increasing or decreasing number of CH2 groups in an aliphatic chain

Question 2

What are the 3 physiochemical properties that homologation affects?

Answer 2

Lipophilicity (Permeability)
PK (ADME)
Size/ Steric (Binding)

Question 3

What is the use of chain branching?

Answer 3

To decrease the lipophilicity and binding of drug to target site

Question 4

Why is linear aliphatic chain more lipophilic than branched chain?

Answer 4

Branched chain need less H2O need for solvation, more energetically favoured

Question 5

What is bioisosteric modification used for?

Answer 5

Produce molecules with same chemical or physical similarities that have similar biological effects

Question 6

What does bioisoteric modification affects?

Answer 6

Structural changes (size, shape, polarizability, H bonding)
Receptor interactions (does not affect lipid and water solubility)
PK changes (ADE)
Metabolism

Question 7

What is the purpose of rigidification?

Answer 7

Reduce conformational mobility by introducing ring formation or bulking groups that restrict conformational changes

Question 8

What is the purpose of peptidomimetics?

Answer 8

Mimic or block the biological effects of a peptide by interacting with the target but do not have the undesirable characteristics of peptides

Question 9

What is the purpose of alkyl substituent?

Answer 9

1. Investigate the effect of chain length and bulk at the binding site
2. Probe the depth and width of the pocket

Question 10

What is the effect of alkyl substituent?

Answer 10

Increase the length and/or the bulk of the R group to take advantage of binding interaction and lead to increase binding affinity.

Question 11

What is the effects of varying substituent on aromatic ring?

Answer 11

probe better interaction at the binding site

Question 12

What is the effect of ring fusion?

Answer 12

1. Increase interaction or selectivity
2. Alter hydrophobic interaction to give better binding affinity

Question 13

Explain extension of structure.

Answer 13

Addition of another functional group to the lead to probe for extra binding interaction at the target

Question 14

What is one common use for structure extension?

Answer 14

Convert agonist to antagonist of receptor or substrate to inhibitor of enzyme

Question 15

What is the simplification of structure used on?

Answer 15

Complex leads derived from natural sources

Question 16

List 4 possible disadvantage of oversimplification of structure.

Answer 16

1. Simplified molecule binds differently to the target
2. Lost of desirable pharmacological activity
3. Appearance/increase in side effects/toxicity
4. Reduced in target selectivity

Question 17

What is the three point contact model of enantiomeric drugs?

Answer 17

1. Acceptor–donor or hydrophobic interaction between aromatic ring of adrenaline and aromatic ring of receptor protein.
2. Hydrogen bond at the alcoholic hydroxyl.
3. Ionic bond between the protonated amino group and aspartic or glutamic carboxylic group of the receptor