Dugga 2 - chapter 13 Flashcards
What can oversimplification lead to?
- Compound becomes too flexible ==> changes binding compared to the original lead compound
- Reduced activicty
- Reduced selectivity
How can you simplify a lead compound?
- Remove asymetric carbon, replace it with a nitrogen.
- Introduce symetri ex via extension of the structure
Variation of substituents can be done in many ways, what are the 4 main substituent focus areas/tactics?
- Introduce alkyl substiuents
- Introduce substituents on aromatic or heteroaromatic rings
- Introduce and vary substiuents to change the PKa of ionizable group
-Introduce substiuents and look at the synergistic effects
How can alkyl substiuents be used to study a lead compund with an excisting alkyl-group (esters, amines, ethers and amides)?
To study if/how already excisting alkyl-functional groups linked are important for binding via interactions with hydrophobic pockets/binding areas
Replace the alkyl-group with:
- A longer and bulkier alkyl to get a sense of the deepth and width of the binding site. If activity increases the hydrophobic interactions are important. OBS maximum 55% of the hydrophobic pocket should be occupied for maximum affinity. Decreased activity indicates that the alkyl group is too bulky and long and blocks interactions.
- Another alkyl group to increase selectivity ex isoprenaline analoge for adrenaline, show affinity for beta receptor
How can substituents on aromatic or heteroaromatic rings be used?
- Introduce substituents with different position of the heteroatom to find better binding interactions ex fits better in a binding region. Changing the position of one electron-withdrawing heteroatom may also affect another atom/functional group in the ring, ex decrease the basicity of an aromatic amine if an electron withdrawing heteroatom is in para position relative to the amine (resonance and inductive effects) rather than in meta position. This would limit the amine to form ionic bonds.
- introduce substiuent with different heteroatoms to investigate how the substiuents steric, hydrophobic and electron properties may affect the activity.
What are some electron withdrawing substiuents/functional groups?
CN
NH3+
NO2
CF3
All have too little electrons or strongly electronegative so they will drag electrons from a structure.
How does an electron withdrawing substituent affect PKa for a ionizable group?
Lowers it.
What are some electron doning substiuents/functional groups?
NR2
NH2
OH
ROR
All have lone pairs that they can donate.
How can varying the position of the substituents change the PKa of ionizable groups in a non-aromatic system?
The closer the substiuent is to the inozable group the greater effect.
What are two ionizable groups? With what amino acids can they interact with?
Amine can be protonated to a charged aminium ion. Asp and Glu
Carboxylic acid can be deprotonated to form a negatively charged carboxylate ion. Arg or Lys.
How can varying position of the substituents change the PKa of ionizable groups in a
aromatic system?
The best position is para position relative to the ionizable group
Mention some ways that extension of the structure will effect binding
- Adding various alkyl or arylalkyl groups to increase interaction with hydrophobic regions.
- Adding polar functional groups to probe for extra H-bonding or ionic interactions.
- Convert an agonist into an antagonist by too strong binding (suicide drug).
How does chain extension/contraction affect binding?
The lead compound studied may not have the ideal chain length for interaction, altering improves binding.
How does ring extension/contraction affect binding?
Expanding or contracting a ring may
- put other rings in different positions relative to each other and may lead to better interactions with specific regions in the binding site.
- Put heteroatoms/functional groups/substiuents in better position Ex cilazaprilat
What is ring variation?
Replace the original ring with a range of other heteroatomic rings of different size and heteroatom positions.
What are me too drugs?
Made with ring variation, gives the same activity.
What are me better drugs?
Made with ring variation, gives the better activity.
What is one advantage substituting an aromatic ring with a heteroaromatic ring?
Introduces possiblity of an extra hydrogen-bonding interaction.
What is a scaffold?
A central ring or ring system that is responsible for orienting substiuents to relevant parts of the binding site.
What is ring fuison?
Introduce a new ring, fused together with an already excisting ring.
How can you performe rigdification of a compund?
Lock a flexible compund in it’s active conformation to a specific receptor/binding site.
What is the possible good effects of rigdification?
- Increase activity since there is no loss in entrophy involved when binding.
- Increase selectivity ==> less side effects
- Increases oral variability
What are the disadvantages of rigdification?
- More complicated to synthesize
- No garantue that the active conformation is kept through out the path towards the target.
- What if the target changes shape?