Drug Design: Optimising binding interactions Flashcards
What are lead compounds from the synthetic world?
• Combination of structure-based rational drug design and chemistry can be used for drug optimisation to produce binding interactions with target
Why would this be needed?
- To increase activity and reduce dose levels
* To increase selectivity and reduce side effects
What are the strategies of optimising binding interactions? (9)
- Vary alkyl substituents
- Vary aryl substituents
- Extension
- Chain extensions / contractions
- Ring expansions / contractions
- Ring variation
- Isosteres
- Simplification
- Rigidification
What may alkyl groups in lead compounds do?
May interact with hydrophobic region in binding site
Varys length and bulk of group to optomize interaction
Also improves binding ability - increased methyl groups - improve hydrophobic interaction and improve binding affinity
What else can varying length and bulk of alkyl groups do?
Introduce selectivity
- for example in adrenergic agents (ß-adrenoceptors over α-adrenoceptors)
Receptor 1 has a larger binding site – so both ligands can fit (large enough to accommodate both)
Receptor 2 binding site cannot fit the 2nd receptor – steric block
Varying alkyl substituents - adrenoceptors
a-Adrenoceptor
• Smaller inside the active centre – less extended
• Adrenaline binds
b-Adrenoceptor
• Adrenaline can bind alpha OR beta – NON-SPECIFIC LIGAND
• Salbutamol – very bulky methyl groups which occupy extended section
• Steric flash – interaction is very thermodynamically unstable - SELECTIVE TO BETA
What is an aryl group?
Functional group derived from a simple aromatic ring.
Substitute to incresse binding affinity
What is extension?
Extra functional groups - to explore target binding site for further binding regions to achieve additional binding interactions - e.g. ACE INHIBITORS
What is chain extension/contraction?
•Useful if a chain is present connecting two binding groups
•Vary length of chain to optimize interactions
Increase/decrease the chain length so it binds more strongly to binding regions
Why is testing drug candidates required?
- Tests are required in order to find lead compounds and for drug optimisation
- Tests can be in vivo or in vitro
- A combination of tests is often used in research programmes
What 2 factors need to be considered during testing?
sufficient activity against the desired target
minimal activity against any other targets to reduce off-target effect
What are in vitro tests carried out on?
- In vitro tests are carried out on target molecules, whole cells, isolated tissues, or isolated organs
- Testing antibacterial agents on microbiological cultures is considered to be in vitro testing
What are in vivo tests carried out on?
- In vivo tests are carried out on living systems such as animals or human volunteers
- The in vivo test for an antibacterial agent involves infecting a test animal with a bacterial strain, then administering the antibacterial agent to the animal to see whether it combats the infection
What is an enzyme assay?
In vitro test
Test to evaluate the level of enzyme inhibition
To evaluate the mode of inhibition (e.g. competitive or non-commpetitive)
To measure IC50
What is IC50?
Concentration of inhibitor in system which reduces activity of target enzyme by 50%
During an enzyme assay, how can you tell if the inhibitor is efficient?
Compare with and without inhibitors present
If activity drops with inhibitor – then inhibitor is efficient
What does IC50 correspond to ?
- IC50 corresponds to the concentration of inhibitor required to reduce enzyme activity by 50%
- The smaller the dose required to achieve the biological effect, the more potent the drug
What is testing with receptors carried out on?
• Carried out on whole cells, tissue cultures, or isolated organs
*not easy to isolate membrane bound receptors as they’re usually integrated into the membrane
Measurements in testing with receptors
- Affinity - strength with which compounds bind to a receptor
- Efficacy - measure of maximum biochemical effect resulting from binding of a compound to a receptor
- Potency - concentration of an agonist required to produce 50% of the maximum possible effect
- The smaller the dose required to achieve the biological effect, the more potent the agonist
What do in vitro tests measure?
The interaction of a drug with the target
More suitable for routine testing than in vivo
• May also be used to test for pharmacokinetic properties of drug candidates (e.g. Caco-2 cell monolayer absorption models)
• Results are easier to rationalise - less factors involved
What is high throughput screening?
Often an automated process
Is an in vitro testing
Carried out on small scale
• It can be carried out on large numbers of compounds in a short time
• It is designed to identify a drug lead within the large library of candidate molecules
Limitations of in vitro tests
- Do NOT evaluate the ability of the drug to reach the target
- Does not demonstrate a physiological or clinical effect
- Does not identify possible side effects
- Does not identify effective prodrugs
What do in vivo tests measure?
An observed physiological effect.
Measure a drugs ability to interact with its target and its ability to reach that target
Can identify possible side effects
• Rationalisation may be difficult due to the number of factors involved
What is drug potency?
concentration of drug required to produce 50% of the maximum possible effect
What is therapeutic ratio/index?
compares the dose level of a drug required to produce a desired effect in 50% of the test sample (ED50) versus the dose level that is lethal to 50% of the sample (LD50)
