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
What is an enone?
An organic compound containing both alkene and ketone functional groups
Are enols acidic or basic?
Acidic
What are benzologues?
What are the 2 different kinds?
Benzologues are analogues that have benzene ring inserted by fusion into the structure for the exploration of potential enhancement in hydrophobic interaction
Linear and angular benzologues have been studied
Explain ring fusion and how it helps in structural modification
Ring fusion can result in increase interaction or increase selectivity.
The fused ring system may recognize an area for better hydrophobic interaction to give better binding affinity
What is ring variation?
What is an advantage of such a structural modification?
If the lead compound has aromatic carbocyclic or aromatic heterocyclic ring, a popular modification strategy is to replace the ring with other aromatic ring system, different ring size or different heteroatoms.
They can lead to improved activity, enhance selectivity or reduced side effects
What is one advantage of replacing a phenyl ring with a heterocycle?
The possibility of an extra H
bonding interaction
What is extension of structure?
This strategy involves the addition of another functional group to the lead to probe for extra binding interaction at the target.
What is the goal of extension of structure?
Often used to probe for hydrophobic region by adding alkyl groups to the lead; these groups can be added to alcohol, phenol, amine or carboxylic acid present in the lead already
What type of functional groups can be added to probe for extra H bonding sites/ ionic interactive sites?
Hydroxyl group, amide, phenol, acid or amine
What type of leads is simplification of structure strategy commonly used on?
Commonly used on complex leads derived from natural sources
What are the real life drug applications of the extension of structure technique?
Frequently, extension strategy is used to convert agonist to antagonist of receptor or substrate to inhibitor of enzyme
What are some possible disadvantages to oversimplification? (4)
- Simplified molecule binds differently to the target
- Loss of desirable pharmacological activity
- Appearance/increase in side effects/toxicity
- Reduced in target selectivity
Why is it important to take note of possible stereoisomers in the drug compounds?
Enantiomeric drugs may elicit differential biological responses toward a target.
Regarding stereo-selectivity, what is the 3-point contact model?
- Acceptor–donor or hydrophobic interaction between the aromatic ring of adrenaline and an aromatic ring of the receptor protein.
- A hydrogen bond at the alcoholic hydroxyl.
- An ionic bond between the protonated amino group and an aspartic or glutamic carboxylic group of the receptor.
