Lecture 3 - Pharmacophores

Question 1

What is a pharmacophore?

Answer 1

Part of the molecular structure that is responsible for the biological or pharmaceutical effect, and its relative position in space

Question 2

How is a pharmacophore identified?

Answer 2

Prepare a number of compounds that differ slightly from the original and study the effect on biological activity.
Remove ability of compound to form a certain bond. If biological activity stays same = not important. If activity drops = bond was formed by pharmacophore

Question 3

What bond does a hydroxyl group form, and how would you test if this was a pharmacophore?

Answer 3

Hydrogen bond
Replace the H with a methyl or ethyl group, which cannot be a hydrogen bond donor. The O can still accept H bonds but the alkyl group should sterically hinder close approach
Or replace the H with an acetyl group, forming an ester, which also cannot hydrogen bond. The large ester group also sterically hinders bonding

Question 4

What bonding does an amine group partake in?

Answer 4

Hydrogen bonding (lone pair on the N acts as an acceptor, and any of the H can act as a donor)
Ionic bonding - at physiological  pH the N gains another H, and a positive charge

Question 5

How would you test if an amine group was a pharmacophore?

Answer 5

Replace an H with an acetyl group, forming an amide group. Makes the N unable to accept a hydrogen bond.

Also means the N cannot accept another H, so cannot gain a positive charge an participate in ionic bonding.

Question 6

What bonding can an aromatic ring partake in?

Answer 6

The electron density can stabilise an ionic bond

Van der Waals with a flat hydrophobic region

Question 7

How would you test if an aromatic ring was a pharmacophore?

Answer 7

Convert the flat ring into a ring fully saturated with H - less surface contact so less van der Waals forces
Or add in a bulky aryl group

Question 8

What interactions do alkenes form, and how would you test if it was a pharmacophore?

Answer 8

Van der Waals and hydrophobic interactions with hydrophobic regions
Hydrogenating it to an alkane prevents these interactions

Question 9

What bonding does a ketone partake in?

Answer 9

Hydrogen bond (as the acceptor)
Dipole-dipole interactions

Question 10

How would you test if a ketone was a pharmacophore?

Answer 10

Reduce the ketone to an alcohol.
Shape changes from trigonal planar to tetrahedral prevents hydrogen bond formation.
Geometrical change in spatial arrangement prevents dipole alignment.

Question 11

What bond does an amide partake in?

Answer 11

The O acts as a hydrogen bond acceptor

Question 12

How would you test if an amide was a pharmacophore?

Answer 12

Hydrolysis of the amide

Or reduce the carbonyl of the amide to CH2, so there is no O to act as hydrogen bond acceptor

Question 13

What is a chemical isostere?

Answer 13

Atom (or group of atoms) with same chemical or physical properties due to number of shells or valency, so can be swapped in place of eachother

Question 14

What are the two types of chemical isostere?

Answer 14

Steric isostere = same size. Atoms in same period

Electronic isostere = same electrical properties. Atoms in same column. Forms same bonds

Question 15

Name 3 isosteres of OH

Answer 15

SH
NH2
CH3

Question 16

Name 3 isosteres of O

Answer 16

S
NH
CH2

Question 17

How are isosteres used to identify a pharmacophore?

Answer 17

Replacing a group with it’s steric isostere and measuring biological activity will tell you if the electronic effects are important
Replacing a group with it’s electronic isostere will tell you if the steric effects are important

Question 18

Why is it important to identify the pharmacophore of a drug?

Answer 18

So you know which parts have flexibility to be changed for optimisation and which should be left

Question 19

Name 6 functional groups that you might consider testing to see if they are the pharmacophore

Answer 19

Hydroxyl
Amine 
Aromatic ring
Alkene 
Ketone
Amide

Question 20

What are 4 features of a drug that need to be optimised?

Answer 20

Activity increase (so the dose can be reduced)
Reduce side effects
Easy/efficient administration
Easy synthesis

Question 21

Name 9 variations that can be made to a lead compound in attempt to optimise it

Answer 21

1. Varying alkyl groups to make them longer/shorter
2. Swap alkyl group for aromatic ring
3. Ring expansion/contraction
4. Ring variations
5. Ring fusions
6. Simplification of structure
7. Rigidification of structure
8. Conformation blockers
9. Isosteres

Question 22

Describe how variation of alkyl groups can optimise a lead compound

Answer 22

Changing the length of an alkyl group can

• improve surface area contact for hydrophobic interactions
• bulk confers selectivity for receptor subtypes
• extensions may utilise unused binding regions

Question 23

Describe how aromatic ring expansion/contraction can optimise a lead compound

Answer 23

Greater number of interactions with a hydrophobic region

Only 5/6/7 sided rings can be easily made by chemists

Question 24

What are the possible ring variations?

Answer 24

Transform an aromatic ring to a heteroaromatic ring e.g replace a C with an N or O
Add in multiple heteroatoms
Try the heteroatoms in different positions

Question 25

Describe how ring fusions can optimise a lead compound

Answer 25

Can provide increased interactions or increased receptor selectivity due to sterics and surface area for interactions

Question 26

Describe how simplification of the structure can optimise a lead compound. Give an example

Answer 26

Strip away non-essential parts, makes it easier/cheaper to synthesise and reduces side effects

Question 27

Describe how rigidification of the structure can optimise a lead compound

Answer 27

Adding in double bonds, amides or aromatic rings into long alkyl chains restricts bond rotation, meaning less ‘attempts’ needed to fit into the active site

Question 28

Describe how conformation blockers can optimise a lead compound

Answer 28

Addition of a methyl substituent into an aromatic ring creates a steric clash between closely located rings, forcing the molecule into a non-planar shape

Question 29

Describe how ring variations can optimise a lead compound

Answer 29

A heteroatom provides an additional binding group, so there is potential for more interactions with the target