3 + 4 Flashcards
Why are lead structures modified?
So that binding interactions between a drug and its target are improved.
What does stronger binding do?
- Lead to greater activity
- Increase selectivity.
Stronger binding to a certain target will improve the selectivity between different targets.
The better the binding to our target, the less we have to worry about it binding to other things.
Explain Alkyl substituents in terms of variation?
Alky groups bound to heteroatoms can be easily varied.
Alkyl groups bound to carbon atoms CANNOT be easily removed and replaced – so a modified full synthesis may be required
The enlargement of an alkyl substituent may lead to stronger binding to such a region.
The overall size may also improve the selectivity of a drug
Explain Aromatic substituents in terms of variation?
Relatively easy to vary the position of substituents on an aromatic ring.
Changing the position of one substituent may affect the electronic properties of another, if they become ortho or para substituted to one another.
Explain Chain Extensions, Ring Expansions, Ring Variation, and Extension by Ring Fusion?
(Structure Extension)
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. Varying chain length may improve drug-target interactions.
Ring Expansions / Contractions:
Altering the size of a ring will affect the orientation of substituents – the same effect as varying substituent pattern.
Binding groups may end up in a better position to bind to the binding site
Ring Variation:
A common strategy employed during analogue synthesis is to replace an aromatic ring with a different heteroaromatic ring This may result in extra hydrogen bonding with the binding site
Extension by Ring Fusion:
A lead structure can also be extended by fusing one ring onto another.
This may introduce selectivity (as in the case of alkyl chain extensions) and also allow for extra van der Waals interactions
Explain how Structural Simplification takes place?
Identification of the pharmacophore can allow us to simplify the structure of analogues, so that they contain only the essential binding regions – makes the synthesis of analogues easier.
What are some negative effects of Structural Simplification?
Change in 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.
Simplification is only useful if the lead is a complex natural target.
Explain Structural Rigidification?
What is the disadvantage of this?
- Locking a molecule into only one conformation by rigidification may improve selectivity
A common strategy is to discover the active binding conformation and then rigidify by incorporating the skeleton into a ring
The disadvantage of this strategy is that the drug targets may be difficult to synthesise
Examples of Rigid functional groups?
Rings, amides, aryl groups and alkynes.
What is the ‘QUANTITATIVE STRUCURE-ACTIVITY RELATIONSHIPS’ (QSAR) approach?
it is attempted to derive a mathematical relationship between physicochemical parameters and biological activity in the form of an equation.
What can the QSAR equation be used to do?
- Predict in advance the activity of an unknown compound
- Derive a structure that exhibits optimum activity. The medicinal chemists knows which type of analogue to prepare; this will cut down on the cost and time taken to develop a drug
- Discover which drug properties have an important role. This may give us information regarding the nature of the active site of an enzyme/receptor
How is partition coefficient measured and why?
Used to determine Hydrophobicity and Lipophilicity.
Measured by investigating a drug’s distribution in an octanol/water mixture.
P = Concentration of drug in octanol / Concentration of drug in water
What are the three stages of drug action?
- Transport of the drug to its site of action
- Stability of the drug
- Binding of the drug to the target active sit
What does each stage of drug action depend on?
Stage 1 – depends largely on membrane permeability – drug’s lipophilicity
Stage 2 – depends on stability – ionisation potential
Stage 3 – depends on the size of a drug and the configuration of the structure.
Equation for Biological Activity?
Biological Activity = lipophilicity + stability + binding
