Drug Design: Biomolecular Target Design Flashcards
What is a good method for tuning binding interactions?
Varying the substituents. Alkyl groups bound to heteroatoms can be easily varied e.g. NR2 to OH,
What is target orientated drug design?
Where a lead structure can be modified so that binding interactions between a drug and its target are improved
Stronger binding leads to greater activity and increases selectively between different targets
Can alkyl groups bound to carbon atoms be varied?
Not very easily as they cannot be easily removed and replaced.
Varying these may require a modified full synthesis which is very difficult and requires more time and money, therefore the easy structures should be made first
Why would we want to vary the size and type of alkyl substituent?
It can be used to probe the size and shape of hydrophobic regions in a target.
The enlargement of an alkyl substituent may lead to stronger binding
What can happen if the drug is bigger and more lipophilic?
The drug may become less selective
How may the overall size of the drug molecule improve its selectivity?
It will no longer be able to bind to receptors which cannot accommodate for the size of the compound. E.g. The larger propyl substituted amine is more selective for receptor 1
Can aromatic substituents be varied?
Yes it is relatively easy to vary the position of substituents on an aromatic ring which can leave them better placed for interaction.
Changing the position of one substituent may affect the electronic properties of another if they become ortho or para substituted to one another.
E.g. Meta substituted amine is a strong base and able to interact with ionic binding groups, when this is moved to para position, the donation of the lone pair of electrons into the ring makes amine now a weak base, and less able to interact with ionic binding groups.
What is structure extension?
Extending the structure of the lead compound.
This may be due to the lead structure not interacting with all possible binding groups in a target.
The addition of extra functionality may be used to probe for extra binding sites.
The addition of extra alkyl or aryl groups may be used to find extra hydrophobic regions
E.g. Adding phenethyl group to the antihypertensive agent on the right led to a great increase in activity
What are some other effects of chain extensions/contractions?
If a lead structure has two binding groups linked by a chain, the length may not be ideal for optimum binding to both sites.
It may therefore be appropriate to vary the chain length to improve drug target interactions.
What a a the effect of ring expansions/contractions?
Altering ring size affects the orientation of substituents.
This essentially gives the same effect as varying the substituent pattern.
Binding groups may end up in a better position to interact with the binding site e.g. Cilazaprat is used clinically as an anti hypertensive. One of the cyclic hexane rings has been enlarged by adding ethyl group, placing the substituents in a more favourable position to interact with the receptor
What is the effect of ring variations?
This is a common strategy employed during analogue synthesis.
This replaces an aromatic ring with a different heteroaromatic ring, which may result in extra H bonding with the binding site.
What is extension by ring fusion?
Where a lead structure is extended by fusing one ring onto another.
This may introduce selectivity (like in the case of alkyl chain extensions) and also allow for extra VDW interactions
E.g. Pronethalol is the result of ring fusion making it more selective for β-adrenergic receptors than adrenaline
Why is structural simplification important?
By identifying the pharmacophore we can simplify the structures of analogues so that they contain only the essential binding regions, making synthesis of analogues much easier.
What are the disadvantages of structural simplification?
May change drug activity. Drastic changes may result in analogues that bind differently leading to different effects.
Loss of selectivity. Simplification may also result in reduced activity and selectivity. Flexible molecules may bind with a number of similar receptors
It is best to simplify in stages and test each compound for activity
When is structural simplification strategy useful?
If the compound is a natural target as these usually have large and complex structures,
