Lecture 3 - Pharmacophores Flashcards
What is a pharmacophore?
Part of the molecular structure that is responsible for the biological or pharmaceutical effect, and its relative position in space
How is a pharmacophore identified?
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
What bond does a hydroxyl group form, and how would you test if this was a pharmacophore?
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
What bonding does an amine group partake in?
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
How would you test if an amine group was a pharmacophore?
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.
What bonding can an aromatic ring partake in?
The electron density can stabilise an ionic bond
Van der Waals with a flat hydrophobic region
How would you test if an aromatic ring was a pharmacophore?
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
What interactions do alkenes form, and how would you test if it was a pharmacophore?
Van der Waals and hydrophobic interactions with hydrophobic regions
Hydrogenating it to an alkane prevents these interactions
What bonding does a ketone partake in?
Hydrogen bond (as the acceptor) Dipole-dipole interactions
How would you test if a ketone was a pharmacophore?
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.
What bond does an amide partake in?
The O acts as a hydrogen bond acceptor
How would you test if an amide was a pharmacophore?
Hydrolysis of the amide
Or reduce the carbonyl of the amide to CH2, so there is no O to act as hydrogen bond acceptor
What is a chemical isostere?
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
What are the two types of chemical isostere?
Steric isostere = same size. Atoms in same period
Electronic isostere = same electrical properties. Atoms in same column. Forms same bonds
Name 3 isosteres of OH
SH
NH2
CH3
Name 3 isosteres of O
S
NH
CH2
How are isosteres used to identify a pharmacophore?
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
Why is it important to identify the pharmacophore of a drug?
So you know which parts have flexibility to be changed for optimisation and which should be left
Name 6 functional groups that you might consider testing to see if they are the pharmacophore
Hydroxyl Amine Aromatic ring Alkene Ketone Amide
What are 4 features of a drug that need to be optimised?
Activity increase (so the dose can be reduced)
Reduce side effects
Easy/efficient administration
Easy synthesis
Name 9 variations that can be made to a lead compound in attempt to optimise it
- Varying alkyl groups to make them longer/shorter
- Swap alkyl group for aromatic ring
- Ring expansion/contraction
- Ring variations
- Ring fusions
- Simplification of structure
- Rigidification of structure
- Conformation blockers
- Isosteres
Describe how variation of alkyl groups can optimise a lead compound
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
Describe how aromatic ring expansion/contraction can optimise a lead compound
Greater number of interactions with a hydrophobic region
Only 5/6/7 sided rings can be easily made by chemists
What are the possible ring variations?
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
Describe how ring fusions can optimise a lead compound
Can provide increased interactions or increased receptor selectivity due to sterics and surface area for interactions
Describe how simplification of the structure can optimise a lead compound. Give an example
Strip away non-essential parts, makes it easier/cheaper to synthesise and reduces side effects
Describe how rigidification of the structure can optimise a lead compound
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
Describe how conformation blockers can optimise a lead compound
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
Describe how ring variations can optimise a lead compound
A heteroatom provides an additional binding group, so there is potential for more interactions with the target
