SAR

Question 1

overview of the types of SAR strategies

Answer 1

1) analoguing

• similar complexity, systematic stepwise approach, modifying original structure
• pros: explore SAR through specific changes
• cons: broadly similar compounds
• strategies: alkyl substitution, aromatic ring as probe, vinyl group and vinylogues, ring expansion/contraction, ring fusion, extension of structure, homologation, chain branching, bioisosterism, bioisosteric replacement, stereoselectivity in biologically active compounds

2) simplification

• disjunctive approach
• pros: remove unnecessary groups and maintain key interactions
• cons: oversimplication
• strategies: simplification, rigidification

3) adding groups

• conjunctive approach, adding completely new functional groups
• pros: extra functional group added to create/probe for new interactions
• cons: increase MW and potentially hydrophobicity
• strategies: peptidomimetics, ring variation

Question 2

alkyl substitution

Answer 2

• uses alkyl substituents as probes
• R groups to investigate effect of chain length and bulk at binding site: methyl, ethyl, propyl, butyl, isopropyl, tert-butyl
• R groups interact with hydrophobic pocket to probe depth and length
• increase length +/- bulk of R group = increase binding affinity +/- selectivity

Question 3

aromatic ring as probe

Answer 3

• change subsitutent on aromatic ring to probe for better interaction at binding site
• alkyl, hydroxyl, halogen

Question 4

vinyl group and vinylouges

Answer 4

• what is vinyl group? CH2-CH-x
• C=O or -OH at x impart different chemical properties
• enone (x = C=o)susceptible to reaction in vivo w GSH

Question 5

simplification of structures

Answer 5

• complex leads from natural sources: remove non-essential parts through structural modification
• problems of oversimplification
  1) bind differently to target
  2) loss of desirable pharmacological activity
  3) appearance/increase in SE/toxicity
  4) reduce in target selectivity

Question 6

ring expansion/contraction

Answer 6

• expand or contract 1 unit at a time

Question 7

ring fusion

Answer 7

• increase interaction/selectivity
• maybe recognise area for better hydrophobic interaction = better binding affinity
• benzylogue used as probe for hydrophobic site
  ** benzene ring inserted by fusion into structure

Question 8

extension of structure

Answer 8

• both analoging and adding groups depending on what type of extension
• addition of another functional group to probe for extra binding interaction to target
  ** hydrophobic for hydrophobic region
  ** hydrophilic for extra H binding site
• convert agonist to antagonist
• convert substrate to inhibitor

Question 9

homologation

Answer 9

• increase/decrease number of CH2 in aliphatic chain
• influences: lipophilicity (membrane permeability), PK, size/steric property (binding)
• identifying process: stepwise change in n value, lowest IC50 = most optimal length

Question 10

chain branching

Answer 10

• effects of branching
  ** branched require lesser water molecules for solvation = more energetically favourable = less lipophilic than linear
• types of branching in aliphatic chain: N-butyl, isobutyl, sec-butyl, tert-butyl
• types of branching in amines: pri, sec, tert amines

Question 11

bioisosterism

Answer 11

• bioesters: groups of molecules w chemical and physical similarities producing broadly similar biological effects
• effects

1) Structural change: size, shape, polarisability, H-bonding
2) receptor interaction: interactive parameters change except for lipid and water solubility
3) PK: moiety for ADME change = change lipophilicity, hydrophilicity, pKa, H bonding
4) metabolism: Affect metabolism if moiety involved in blocking/aiding metabolism

Question 12

bioesteric replacement

Answer 12

replace atoms/groups that demonstrate similar physicochemical properties

Question 13

stereoselectivity in biologically active comounds

Answer 13

• explore if there is difference in activity between enantiomers
• 3 point contact model
  ** 3 point contact required between reacting molecule and binding partner for reaction to occur
  ** highlight importance of spatial orientation and complementary molecule shapes
• ED50: effective dose 50%
• LD50: lethal dose 50%

Question 14

rigidification

Answer 14

• reduce conformational mobility with ring/bulking groups so that:

1) better binding, less off target effect
2) avoid metabolic enzyme = more stable

Question 15

peptidomimetics

Answer 15

• peptides not good targets cuz poor F
• peptidomimetics mimic/block biological effect of peptide by interacting with target but without undesirable characteristics
• goal: replace as much of peptide backbone with non peptide fragment while maintaining pharmacophoric groups
• non peptidomimetic: basically replaced all peptides so no longer a peptide anymore

Question 16

ring variation

Answer 16

• interchange ring with another aromatic system
• maybe better activity, enhanced selectivity, reduced SE