Roles of functional groups

Question 1

What is a functional group?

Answer 1

Functional group is portion of a molecule that is a recognizable/classified group of bound atoms.
The functional group gives the molecule its properties, regardless of what molecule contains it.
They are centres of chemical reactivity.

Question 2

What is SAR?

Answer 2

Structure Activity Relationships.

- studies which parts of the molecule are important to biological activity and which are not.

Question 3

Why is SAR important?

Answer 3

Recognising functional groups and the intermolecular bonds that they can form is important in understanding how a drug might bind to a target.

Question 4

What is the role of OH functional groups?

Answer 4

Ability to form hydrogen bonds.

Question 5

How many bonds does OH have?

Answer 5

3 potential H bonds
2 hydrogen bond acceptors = on oxygen
1 hydrogen bond donor = on hydrogen

Question 6

Describe H-bonding in an ether group.

Answer 6

Ether might hinder or prevent the hydrogen bonding.
There is no hydrogen atom present.
The steric bulk of CH3 hinders close approach.

Question 7

Describe H-bonding in an ester group.

Answer 7

There is no hydrogen atom present.

The bulk of acyl hinders close approach.

Question 8

Describe the binding of aromatic rings.

Answer 8

Aromatic rings = planar, hydrophobic structures - involved in VdW and hydrophobic interactions with the flat hydrophobic regions of the binding site.

Question 9

Describe the binding of cyclohexane rings (analogue).

Answer 9

A cyclohexane analogue will be not bind as well as an aromatic ring as the ring is no longer planar/flat. The axial protons of the cyclohexane can interact weakly with the hydrophobic binding region. But the protons serve as buffers to keep the rest of the cyclohexane ring at a distance.
Cyclohexane would be incapable of fitting into binding site as it is bulkier.

Question 10

How can aromatic rings interact with ammonium ions?

Answer 10

Through induced dipole interactions or hydrogen bonding

- not possible for cyclohexane analogue.

Question 11

Describe the binding of alkenes.

Answer 11

Alkenes are planar and hydrophobic so interact with the binding site through VdW and hydrophobic interactions.
Saturated alkyl region is bulky and cannot approach binding region so closely.

Question 12

Describe the binding of aldehydes and ketones.

Answer 12

Both are planar.
They interact with the binding site through H-bonding where the carbonyl oxygen acts as a HBA - two interactions are possible due to two lone pairs of electrons on the oxygen.
The carbonyl group can have a dipole-dipole interaction with the binding site.

Question 13

How does the geometry change when ketone is reduced to alcohol?

Answer 13

Planar to Tetrahedral

Question 14

What is the effect of changing from planar to tetrahedral in ketone to alcohol?

Answer 14

Geometry change like this will weaken any existing H-bonding interactions and weaken any dipole-dipole interactions.

Question 15

Why are aldehydes less common in drugs?

Answer 15

Because they are more reactive and susceptible to oxidation.

Question 16

Describe the bonding of amines.

Answer 16

There are primary, secondary and tertiary amines.
H-bonding can take place. The N atom has a lone pair of electrons hence acts as a HBA.
In primary and secondary amines, the H atoms act as HBDs.

Question 17

What happens to binding when amines are protonated?

Answer 17

When protonated, N cannot act as HBA but can still act as a H bond donor as H atom will not be ionised.

Question 18

How to test if ionic or H-bonding interactions are taking place in an amine?

Answer 18

Amide analogue is studied.
- this will prevent N acting as an HBA and N’s lone pair will be interacting with the carbonyl group. This interaction prevents protonation of N and rules out possibility of ionic interactions.

Question 19

Describe the binding role of amides.

Answer 19

Amides interact by H-bonding.
Carbonyl oxygen acts as HBA - forms two H-bonds.
N cannot act as HBA because it interacts with the neighbouring carbonyl group.
Primary and secondary = form H-bond via H = HBD.

Question 20

What is the geometry of amide?

Answer 20

Planar - hence will not rotate.

Question 21

Describe the binding role of quaternary ammonium salts.

Answer 21

Quaternary ammonium salts are ionised and can interact with COO- group (carboxylate).
There is a possibility for an induced dipole interaction with aromatic rings in the binding site.
Induced because positively charged N can distort the pi electrons of the aromatic ring.

Question 22

How can the interactions in the quaternary ammonium salts be tested?

Answer 22

Tested by synthesising an analogue that has a tertiary amine group than the quaternary ammonium salt group. Converting amine to amide will prevent protonation.

Question 23

Describe the binding role of a carboxylic acid.

Answer 23

Carboxylic acids bond via H-bonds. Due to oxygens being HBAs and H being HBD. Oxygen has two lone pairs (overall 4 HBA).

Question 24

Describe the binding of carboxylate ion.

Answer 24

COO- has ionic interactions and oxygen acts as strong hydrogen bond acceptor.
COO- has been found to be a good ligand for zinc ions in cofactors.

Question 25

How is the interactions in carboxylate ions and carboxylic acids tested?

Answer 25

Analogues such as esters, primary amides, primary alcohols and ketones can be synthesised and tested.

Question 26

Describe the binding role of esters.

Answer 26

Ester group has potential to interact with a binding site as a H-bond acceptor only due to presence of two lone pairs on O atoms.
CO group more likely to act as HBA than the OH as it is sterically less hindered and has a greater electron density.

Question 27

How is the importance of CO group in esters tested?

Answer 27

By testing an equivalent ether.

Question 28

What is the issue if the lead compound/drug contains an ester group?

Answer 28

Esters are susceptible to hydrolysis by esterases in vivo hence drug might have short time in vivo.
- but electronic factors can be manipulated to aid in stability of esters for in vivo use.

Question 29

Esters that are susceptible to metabolic hydrolysis is important. Why is this a benefit?

Answer 29

Esters which are susceptible can be used deliberately to mask a polar group such as COOH, OH, OHPh to achieve better absorption from GI tract.
Once in blood, ester is hydrolysed to release active drug (acts as prodrug).

Question 30

Describe the binding of alkyl/aryl halides.

Answer 30

Drug containing alkyl halide = likely to react with any nucleophilic group (as halide is electron withdrawing) and will be bound by a covalent bond = an alkylation reaction.
Aryl halides do not act as alkylating agents.
Halides change the property of the aromatic ring (e withdrawing).
Cl and Br halogen substitutions may interact favourably with hydrophobic pocket and form poor H-bond as an acceptor.

Question 31

How to test the importance of alkyl/aryl halides in drugs?

Answer 31

Test of aliphatic and aromatic analogues lacking halogen substituents and prepare to test whether halogen has importance in activity of lead compound.

Question 32

What is the problem in using alkyl/aryl halides in drugs?

Answer 32

Drug is likely to alkylate macromolecules which have a nucleophilic group. It will be non-selective and has side effects hence reserved for life-threteaning illnesses such as cancer.

Question 33

What ion is the thiol group a good ligand for?

Answer 33

Thiol = S-H

good ligand for zinc ion.

Question 34

How to test for important of thiol group?

Answer 34

Test the corresponding alcohol if the lead compound is a thiol group.

Question 35

How can ether importance be tested?

Answer 35

Tested by increasing the size of the neighbouring alkyl group to see whether it diminished the ability of the ether group to take part in H bonding.

Question 36

What group can influence the electronic property of the molecule?

Answer 36

Nitro group = NO2.

Question 37

What can alkynes do to a molecule/lead compound?

Answer 37

Restrict the shape or conformation of the molecule.

Question 38

How can the relevance of an alkyl substituent be determined?

Answer 38

By synthesising an analogue which lacks the substituent.

Question 39

Describe the binding of heterocycles.

Answer 39

Heterocycles interact by VdW forces of attraction and hydrophobic interactions.
Heteroatoms present in the structure for hydrogen bonds or ionic interactions.

Question 40

How can importance of heterocycles be tested?

Answer 40

By synthesising analogues containing an aromatic ring or different heterocyclic rings to explore whether all heteroatoms present are necessary.

Question 41

What is resonance-assisted H-bonding?

Answer 41

In a heterocyclic ring, the strength of the H-bond donor is enhanced by H-bond acceptor and vice versa.

Question 42

What are isosters?

Answer 42

Atoms or groups of atoms which have the same valency and which have chemical or physical similarities.

Question 43

Why are isosters useful?

Answer 43

They can be used to determine whether a particular group is an important binding group or not by altering the character of the molecule in a controlled way.

Question 44

Describe the testing procedures for SAR of compounds.

Answer 44

When investigating SAR for drug-drug binding interactions, biological testing should involve in vitro tests.

• For inhibition studies = isolated enzymes.
• For binding studies = membrane-bound receptors on whole cells.

If in vivo carried out, results may be unclear due to loss of activity due to inability of drug reaching its target. But in vivo testing may show functional groups that are important for protecting or assisting drug through body.

Question 45

What is a pharmacophore?

Answer 45

The pharmacophore summarizes the important binding functional groups, which are required for activity, and their relative positions in space with respect to each other.

Question 46

What is an active conformation?

Answer 46

Conformation that is recognised and bound to the binding site.