Drug design Flashcards
What are the IDEAL characteristics of a drug for oral delivery?
Drug design
Limpinskis rule:
- LogP <_ 5
- Less than 11 H-bond accepting groups
- Less than 6 H-bond donating groups
- Molecular weight less than or equal to 500 [weight <_500]
For absorption in the GIT
What is a Pro-drug?
Drug design
A drug that is inactive in-vitro (outside of the body) but active in-vivo.
what is IC_50
Drug design
The CONCENTRATION of a drug needed to inhibit a biological process by HALF.
What is the difference between pharmacodynamics and pharmacokinetics ?
Pharmacodynamics focuses on the effects of the drug on the body and its target whereas Pharmacokinetics focuses on what the body does to the drug as it is processed (LADME)
Antagonist to agonist comparison
They feature the same functional groups but antagonists tend to be larger
Agonist MOA
- Bind to receptor.
- The binding causes an ‘induced-fit’ reaction.
- Conformational change to the receptor occurs.
- Causes the activation of a secondary messenger.
Agonist remains unchanged
Antagonist MOA
- Binds to the receptor.
- Does NOT cause a conformation change.
What is a pharmacophore?
A molecular feature that is necessary for a specific action.
What happens to a tertiary amine in physiological pH?
It is protonated into a quartenary amine (with a possitive charge)
What happens to a carboxylic acid in physiological pH?
It is deprotonated into a O=O-R (with a negative charge)
Hydrogen bond donor
Also known as a proton donor, is an electronegative atom {N, O, F} that is covalently bonded to a hydrogen.
Hydrogen bond acceptor
When an electronegative species has an available lone pair of electrons.
What is important to remember when altering the structure of a drug?
To make only one change at a time in order to allow observation of possible changes.
If there are multiple changes then we don’t know which change caused the effect.
What functional groups are CONSIDERED BASIC ?
- Guanidine [pKa13.6]
- Tertiary amine [~pKa10]
- Imidazole[pKa 6.8]
- Pyridine [pKa 5.2]
- Aniline [pKa 4.6]
Generally speaking, only pKa 7 and above are considered basic
Is pyridine’s lone pair readily given away?
Yes, because the while the Nitrogen atom is part of the aromatic structure, the lone pair is not included in the aromaticity and therefore is not included in the conjugation.
This means that it is readily given away.
Is aniline’s nitrogen lone pair readily given away
No, because of the angle of the pair of electrons to the conjugated system they are only PARTIALLY involved and therefore they are LESS READILY given away.
In what way can you change a drug molecule?
- Remove a group
- Change a group to another
- Change 3D shape -> change the stereochemistry
- Add double bonds -> Increase rigidity
- Chain extension
Which level of structure are alpha helixes involved in?
Secondary structure
Primary structure
A linear chain/sequence of amino acids called the backbone and residues which allow additional hydrogen bonding .
There is a certain orderthat the backbone chain is formed in.
Secondary structure
The hydrogen bonds between the peptide backbones ->[Residues]
The two types of secondary structures are…
* Alpha helix
- The hydrogen bonds form a ‘coil’
* Beta-pleated sheet
Tertiary structure
The 3D folding of the chains into each other creating a folded sub-unit.
Generally, upheld by external hydrophilic hydrogen , ionic and internal hydrophobic interactions
Quaternary ammoniums are what tertiary amines turn into in physiological pH.
How can we change the structure to determine SAR importance.
IONIC INTERACTIONS -SAR
Replace nitrogen with carbon. This will help determine whether ionic interaction is essential to the activity we want.
This..
* has the same shape [tetrahedral]
* No charge.
If the molecule is still active then we can simplify this group to allow for passing through membranes more easily.
IONIC INTERACTIONS -SAR
How can we determine SAR importance of tertiary & secondary amines
IONIC INTERACTIONS -SAR
Both tertiary and secondary amines are protonated in-vivo allowing for ionic interactions.
So change the amine into an amide.
Why:
Amides cannot be protonated as they do not have an avaliable lone pair of electrons.
If the drug molecule is still active then this group can also be simplified.
IONIC INTERACTIONS -SAR
How can we determine the SAR importance of a carboxylic acid in a drug molecule ?
IONIC INTERACTIONS -SAR
The carboxylic acid is de-protonated in-vivo. Resulting in a negative charge (allows ionic interactions).
You can:
* Replace it with an aldehyde.
* Replace it with an aliphatic alcohol.
* Replace it with an ester.
The aldehyde and alcohol do not have a proton to lose. Ergo they cannot be de-protonated in the body.
The ester is the least favourable as it changes the size of the molecule.
The alcohol can be de-protonated only in highliy basic conditions.
IONIC INTERACTIONS -SAR
How do we determine the SAR importance of a phenol or alcohol in a drug molecule ?
H-BONDING INTERACTIONS -SAR
Alcohols can have both hydrogen bond acceptors AND donors.
Change the alcohol into an ether or ester.
This removes the H-bond donor (H) and reduces the H-bond acceptor activity.
Ergo if the activity ceases THEN the H-bond donor is essential for the specific effect.
H-BONDING INTERACTIONS -SAR
How do we determine the SAR importance of an aromatic structure ?
SAR
Aromatic rings allows for π-π stacking.
Simply change the aromatic structure to a non-aromatic one.
[e.g. Benzene =>Cyclohexane]
The hydrophobic interactions of the aromatic structure are essential IF the activity stops after this change.
SAR
How do we determine the SAR importance of ketones and aldehydes in a drug molecule ?
H-BONDING INTERACTIONS -SAR
The oxygen in the carbonyl is a H-bond acceptor.
Change the molecule into an alcohol.
The alcohol will still have a H-bond acceptor but due the shape of the alcohol molecule the hydroxyl group is further away.
=Reducing the potential of the h-bond acceptor.
H-BONDING INTERACTIONS -SAR
How can we determine the SAR importance of an Ester ?
H-BONDING INTERACTIONS -SAR
Both oxygens in the ester can act as acceptors. However, the carbonyl oxygen is more likely to accept a proton.
Change the Ester into an ether. This deducts the carbonyl h-bond acceptor.
H-BONDING INTERACTIONS -SAR
What is Rigidification ?
Rigidification is the addition of double bonds or ring structures to a molecule to reduce the conformations possible -> INCREASE SELECTIVITY
It is a beneficial change for drug molecules.
We do not want a drug molecule to be able to bind into multiple receptors -> Lots of side effects.
Flexible molecules lack selectivity
What is chain extension ?
- The maximising of van der waal interactions by lengthening carbochains.
- Commonly used for antagonists
How can you change a chemical structure to allow a faster rate of absorption but retain the biological activity at the receptor ?
A pro-drug approach would be suitable to enhance its ability to cross the membrane.
If there is a carboxylic acid:
Change it to a long chain ester to increase hydrophobicity. [UNLESS CARBOXYLIC ACID IS ESSENTIAL TO ACTIVITY]
