IC9- Strategies for SAR studies

Question 1

What are the 9 strategies for structural modifications?

Answer 1

1. Variation of substituents
2. Chain extension/ contraction
3. Ring expansion/ contraction
4. Ring variation
5. Ring fusion
6. Extension of the structure
7. Isosteric replacement
8. Simplification of the structure
9. Stereoisomers

Question 2

What are homologues?

Answer 2

Homologues belong to a series of compounds with increasing OR decreasing number of CH2
groups in an aliphatic chain

Question 3

What 3 factors does homologation influence?

Answer 3

1. Lipophilicity which affects permeability
2. Pharmacokinetics properties which affects ADME
3. Size/ steric property which affects binding at the target site

Question 4

For chain branching, which is more lipophilic- the aliphatic chain or the branched chain?

Explain why

Answer 4

Linear aliphatic chain is more
lipophilic than branched chain
because branched chain
requires less water molecule
for solvation therefore is
energetically more favourable

Question 5

Chain branching affects physicochemical properties of the molecule. What is the consequence?

Answer 5

It affects binding to the target site

Question 6

What is the concept of isosterism?

Answer 6

When two elements possessing an identical peripheral electronic distribution, they will also possess similar chemical properties

Question 7

What are bioisosteres?

Answer 7

Groups or molecules which have chemical and physical similarities producing broadly similar biological effect

Question 8

What is the advantage of bioisosteres?

Answer 8

Allows for exploration of chemical space within a class of therapeutics

Question 8

Elaborate on the effect of bioisosteric modification on structural changes

Answer 8

If the group is involved in structural role, then its
replacement may affect the size, shape, polarizability and H bonding

Question 8

What are the 4 effects of bioisosteric modifications?

Answer 8

1. Structural changes
2. Receptor interactions
3. Pharmacokinetic changes
4. Metabolism

Question 8

Elaborate on the effect of bioisosteric modification on receptor interactions

Answer 8

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

Question 8

Elaborate on the effect of bioisosteric modification on metabolism

Answer 8

If the moiety is involved in blocking or aiding metabolism, the bioisostere may affect the metabolism

Question 8

What is rigidification?

Answer 8

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)

Question 8

Is it possible for conformational constrained molecules to have different affinity for separate targets?

Answer 8

Yes

Question 8

Elaborate on the effect of bioisosteric modification on pharmacokinetic changes

Answer 8

If the moiety replaced is essential for ADE, then lipophilicity, hydrophilicity, pKa and H bonding may be affected.

Question 8

What do peptides generally not make good drug candidates?

Answer 8

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.

Question 9

What are peptidomimetics?

Answer 9

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)

Question 9

What can you say about conformational constrained molecules in terms of metabolic enzyme targets?

Answer 9

Conformational constrained molecules may not be
target of metabolic enzyme, therefore they before
more metabolically stable

Question 10

What is the goal of peptidomimetics?

Answer 10

To replace as much of the peptide backbone as possible with non peptide fragment while maintaining the pharmacophoric groups

Question 10

What is alkyl substitution?

Answer 10

Refers to the replacement or exchange of a hydrogen atom in a molecule with an alkyl group (ref to slide 13 of eL)

Question 10

How can alkyl substitution be used to help in determining characteristics of a binding pocket? (2)

Answer 10

1. 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
2. Larger groups increase the bulkiness of the compound and this may also confer selectivity of the drug for the target → less off-target effects

Question 10

Explain vinyl group and its vinylogues

Answer 10

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)

Question 10

How is ring expansion/ contraction done?

Answer 10

Exploring whether expanding or contracting the ring by 1 unit at a time will affect the biological activity

Question 10

How may varying the substituent on the aromatic ring help with interaction at binding site?

What are the possible substituents we can vary?

Answer 10

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

Question 10

What is an enone?

Answer 10

An organic compound containing both alkene and ketone functional groups

Question 10

Are enols acidic or basic?

Answer 10

Acidic

Question 11

What are benzologues?

What are the 2 different kinds?

Answer 11

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

Question 11

Explain ring fusion and how it helps in structural modification

Answer 11

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

Question 12

What is ring variation?

What is an advantage of such a structural modification?

Answer 12

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

Question 13

What is one advantage of replacing a phenyl ring with a heterocycle?

Answer 13

The possibility of an extra H
bonding interaction

Question 14

What is extension of structure?

Answer 14

This strategy involves the addition of another functional group to the lead to probe for extra binding interaction at the target.

Question 15

What is the goal of extension of structure?

Answer 15

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

Question 16

What type of functional groups can be added to probe for extra H bonding sites/ ionic interactive sites?

Answer 16

Hydroxyl group, amide, phenol, acid or amine

Question 17

What type of leads is simplification of structure strategy commonly used on?

Answer 17

Commonly used on complex leads derived from natural sources

Question 17

What are the real life drug applications of the extension of structure technique?

Answer 17

Frequently, extension strategy is used to convert agonist to antagonist of receptor or substrate to inhibitor of enzyme

Question 18

What are some possible disadvantages to oversimplification? (4)

Answer 18

• Simplified molecule binds differently to the target
• Loss of desirable pharmacological activity
• Appearance/increase in side effects/toxicity
• Reduced in target selectivity

Question 19

Why is it important to take note of possible stereoisomers in the drug compounds?

Answer 19

Enantiomeric drugs may elicit differential biological responses toward a target.

Question 20

Regarding stereo-selectivity, what is the 3-point contact model?

Answer 20

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