IC8 Structural modifications in SAR Flashcards
What are the 11 different types of structural modification that we have learnt?
- Homologation
- Chain branching
- Bioisosterism
- Rigidification
- Peptidomimetics
- Alkyl substitution
- Ring expansion
- Ring fusion
- Ring substitution
- Ring variation
- Extension of structure
- Simplification of structure
What is homologation?
Homologation - increasing or decrease the number of CH2 group in a series of compounds
How does homologation affect a series of compounds?
It affects:
1. Lipophilicity - affects permeability
2. Pharmacokinetics
3. Size - affects binding at target site
How is chain branching different from linear chains?
Linear aliphatic chains are more lipophilic than branched chains - as branched chains require lesser water molecules for solvation.
Chain branching also affects physicochemical properties & binding to target site.
E.g of branching:
1. n-butyl: isobutyl, sec-butyl, tert-butyl
2. Amines: primary, secondary & tertiary amines
What is bioisosterism?
Bioisosterism - groups or molecules which have chemical and physical similarities that produce broadly similar biological effects.
What are the types of bioisosteric modifications?
The types of bioisosteric modifications are:
- Structural changes
- If the group is involved in structural role, its replacement may affect size, shape, polarizability & H bonding - Receptor interactions
- If a group that interacts w a receptor is replaced by a bioisostere, all interactive parameters may change except for lipid & water solubility - PK changes
- Lipophilicity, hydrophilicity, pKa & H bonding may be affected - Metabolism
- Metabolism may be affected if the change made involves a group that helps to block or aid metabolism
What is rigidification?
Rigidification - A reduction is a compound’s conformational mobility
How is rigidification usually done?
By introducing ring formations or bulky groups
Conformationally constrained molecules may not be the target of metabolic enzymes, resulting in increased stability
What are peptidomimetics?
Peptidomimetics are compounds that mimic or block the biological effect of a peptide by interacting with the target, but do not have the undesirable characteristics of peptides
What is the goal of peptidomimetics?
To replace as much of the peptide backbone as possible with non-peptide fragment, while maintaining the pharmacophoric groups.
What is alkyl substitution?
Alkyl substitution is when a functional group on the lead compound is replaced with an alkyl group
How can alkyl substitution be useful?
Alkyl substitution can be used to determine the depth and width of a receptor site.
If the alkyl group interacts with a hydrophobic region within the receptor binding site, we can adjust the length of the alkyl group or branch out the alkyl group to test depth and width.
Larger groups can increase the bulkiness of the compound & improve selectivity.
What is ring expansion/contraction?
When a lead compound has a ring structure, we can expand or contract the ring by 1 unit at a time and see how it affects the activity.
What is ring fusion?
It is when another ring is added to a ring structure in a lead compound.
This can help to increase interaction or increase selectivity.
What is Ring variation?
Ring variation refers to replacing a ring structure in a lead compound with other aromatic ring system.
For example, a benzene ring is replaced with a pentene ring or a pyrimidine ring to see how it affects activity.
