IC9- Strategies for SAR studies Flashcards
What are the 9 strategies for structural modifications?
- Variation of substituents
- Chain extension/ contraction
- Ring expansion/ contraction
- Ring variation
- Ring fusion
- Extension of the structure
- Isosteric replacement
- Simplification of the structure
- Stereoisomers
What are homologues?
Homologues belong to a series of compounds with increasing OR decreasing number of CH2
groups in an aliphatic chain
What 3 factors does homologation influence?
- Lipophilicity which affects permeability
- Pharmacokinetics properties which affects ADME
- Size/ steric property which affects binding at the target site
For chain branching, which is more lipophilic- the aliphatic chain or the branched chain?
Explain why
Linear aliphatic chain is more
lipophilic than branched chain
because branched chain
requires less water molecule
for solvation therefore is
energetically more favourable
Chain branching affects physicochemical properties of the molecule. What is the consequence?
It affects binding to the target site
What is the concept of isosterism?
When two elements possessing an identical peripheral electronic distribution, they will also possess similar chemical properties
What are bioisosteres?
Groups or molecules which have chemical and physical similarities producing broadly similar biological effect
What is the advantage of bioisosteres?
Allows for exploration of chemical space within a class of therapeutics
Elaborate on the effect of bioisosteric modification on structural changes
If the group is involved in structural role, then its
replacement may affect the size, shape, polarizability and H bonding
What are the 4 effects of bioisosteric modifications?
- Structural changes
- Receptor interactions
- Pharmacokinetic changes
- Metabolism
Elaborate on the effect of bioisosteric modification on receptor interactions
If a group that interacts with a receptor is replaced by a bioisostere, all the interactive parameters may change except for the lipid and water solubility
Elaborate on the effect of bioisosteric modification on metabolism
If the moiety is involved in blocking or aiding metabolism, the bioisostere may affect the metabolism
What is rigidification?
Molecules with several rotatable bonds can give rise to many conformations. However, only limited conformations can be accommodated at the target site – active conformations.
Rigidification reduces conformational mobility, and this is usually developed by introducing ring formation or bulking groups that restrict conformational changes (or adding a double bond)
Is it possible for conformational constrained molecules to have different affinity for separate targets?
Yes
Elaborate on the effect of bioisosteric modification on pharmacokinetic changes
If the moiety replaced is essential for ADE, then lipophilicity, hydrophilicity, pKa and H bonding may be affected.
What do peptides generally not make good drug candidates?
Peptides do not generally make good drug candidates as they are readily hydrolysed in the GI tract and serum, therefore they have poor bioavailability and are rapidly excreted.
What are peptidomimetics?
Peptidomimetics are compounds that mimic or block the biological effects of a peptide by interacting with the target but do not have the undesirable characteristics of peptides (such that the modifications make the enzyme unable to recognise it)
What can you say about conformational constrained molecules in terms of metabolic enzyme targets?
Conformational constrained molecules may not be
target of metabolic enzyme, therefore they before
more metabolically stable
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?
Refers to the replacement or exchange of a hydrogen atom in a molecule with an alkyl group (ref to slide 13 of eL)
How can alkyl substitution be used to help in determining characteristics of a binding pocket? (2)
- If the R group interacts with a hydrophobic pocket, a range of R groups will help to probe the depth and width of the pocket. Can take advantage of binding interaction to help increase binding affinity
- Larger groups increase the bulkiness of the compound and this may also confer selectivity of the drug for the target → less off-target effects
Explain vinyl group and its vinylogues
The double bond when conjugated with carbonyl group or the hydroxyl group can impart different chemical properties to the molecule
The enone is susceptible to reaction in vivo with glutathione (GSH)
How is ring expansion/ contraction done?
Exploring whether expanding or contracting the ring by 1 unit at a time will affect the biological activity
How may varying the substituent on the aromatic ring help with interaction at binding site?
What are the possible substituents we can vary?
Varying the substituents on an aromatic ring is relatively simple to probe better interaction at the binding site (can also vary the same functional group at different substituent positions on the ring → positional isomerism)
The substituent could be alkyl group, hydroxyl group or halogen
