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KOKN01 - Medicinal chemistry > Dugga 2 - chapter 13 > Flashcards

Dugga 2 - chapter 13 Flashcards

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1
Q

What can oversimplification lead to?

A
  • Compound becomes too flexible ==> changes binding compared to the original lead compound
  • Reduced activicty
  • Reduced selectivity
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2
Q

How can you simplify a lead compound?

A
  • Remove asymetric carbon, replace it with a nitrogen.
  • Introduce symetri ex via extension of the structure
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3
Q

Variation of substituents can be done in many ways, what are the 4 main substituent focus areas/tactics?

A
  • 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

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4
Q

How can alkyl substiuents be used to study a lead compund with an excisting alkyl-group (esters, amines, ethers and amides)?

A

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
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5
Q

How can substituents on aromatic or heteroaromatic rings be used?

A
  • 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.
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6
Q

What are some electron withdrawing substiuents/functional groups?

A

CN
NH3+
NO2
CF3

All have too little electrons or strongly electronegative so they will drag electrons from a structure.

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7
Q

How does an electron withdrawing substituent affect PKa for a ionizable group?

A

Lowers it.

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8
Q

What are some electron doning substiuents/functional groups?

A

NR2
NH2
OH
ROR

All have lone pairs that they can donate.

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9
Q

How can varying the position of the substituents change the PKa of ionizable groups in a non-aromatic system?

A

The closer the substiuent is to the inozable group the greater effect.

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10
Q

What are two ionizable groups? With what amino acids can they interact with?

A

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.

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11
Q

How can varying position of the substituents change the PKa of ionizable groups in a
aromatic system?

A

The best position is para position relative to the ionizable group

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12
Q

Mention some ways that extension of the structure will effect binding

A
  • 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).
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13
Q

How does chain extension/contraction affect binding?

A

The lead compound studied may not have the ideal chain length for interaction, altering improves binding.

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14
Q

How does ring extension/contraction affect binding?

A

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
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15
Q

What is ring variation?

A

Replace the original ring with a range of other heteroatomic rings of different size and heteroatom positions.

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16
Q

What are me too drugs?

A

Made with ring variation, gives the same activity.

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17
Q

What are me better drugs?

A

Made with ring variation, gives the better activity.

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18
Q

What is one advantage substituting an aromatic ring with a heteroaromatic ring?

A

Introduces possiblity of an extra hydrogen-bonding interaction.

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19
Q

What is a scaffold?

A

A central ring or ring system that is responsible for orienting substiuents to relevant parts of the binding site.

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20
Q

What is ring fuison?

A

Introduce a new ring, fused together with an already excisting ring.

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21
Q

How can you performe rigdification of a compund?

A

Lock a flexible compund in it’s active conformation to a specific receptor/binding site.

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22
Q

What is the possible good effects of rigdification?

A
  • Increase activity since there is no loss in entrophy involved when binding.
  • Increase selectivity ==> less side effects
  • Increases oral variability
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23
Q

What are the disadvantages of rigdification?

A
  • 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?
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24
Q

Conformational blockers

A
25
Q

Rigdification through intramolecular bonds, what are the types of bonds targeted in this tactic?

A
  • Hydrogen bonds, ex two functional groups on one molecule creates a ring.
  • Pi-Pi bonds between aromatic/heteromatic rings
26
Q

What is structure-based drug design an molecular modeling?

A

Use of X-ray crystallography with the tarhet protein and a known antagonist to get good insight of a binding site.

27
Q

For what proteins can’t we use structure based drug design?

A

Membrane-bround proteins since they are hard to isolate.

28
Q

What are the limits of of molecular modeling designed drugs?

A
  • May not be able to synthesise them
  • The design only takes the binding site into consideration.
  • Binding sites can change in unpredicteble ways.
29
Q

Element of luck and inspiration

A
30
Q

Multi-target drug discovery, why is it a good idea and what are the two approaches?

A

Reduce the number of drugs a patient needs

  • Design agents from known drugs and pharmacophores (Bredda)
  • Start from a lead compound that has activity for a broad range of targets and narrow it down to the desired targets (Smalna av)
31
Q

What are the cons of dimeric structure of known drugs.

A

Disadvantage: increased number of functional groups and rotable bonds ==> may make the drug not orally active.

32
Q
A
33
Q

Homodimeric vs heterodimeric

A
34
Q

What is a chimeric drug?

A

A drug that contians key pharmacophore features from two different drugs. ex 2-methoxyesteradiol and colchicine. This may improve pharmacokinetic properties compared to when they were singles.

35
Q

What is a promiscuous ligand/ dirty drug

A

A drug that can bind to alot of different targets. Linear polyamines are one example of such drug

36
Q

What is Pharmacodynamic?

A

The interaction of the drug with its target in order to produce the desired pharmacological effect.

37
Q

What is the aim of studying SAR (Structure - Activity Relationship)?

A

Identify those part of the molecule that are important to biological activity and those that are not.

There are two focuses of SAR:

  • Pharmacodynamic - which groups that act as binding groups with the target.
  • Pharmacokinetic - which groups that assist or protect the drug on its journey through the body
38
Q

What binding roles are important to focus on?

A
  • Binding role of phenols and alcohols
  • Binding role of aromatic rings
  • Binding role of alkenes
  • Binding role of ketones and aldehydes
    -Binding role of amines
    -Binding role of amides
  • Binding role of quaternary ammonium salts
  • Binding role of carboxylic acids
  • Binding role of esters
  • Binding role of alkyl and aryl halides
  • Binding role of thiols and ethers
  • Binding role of phosphates, phosphonates and phosphinates
  • Binding role of other functional groups
  • Binding role of alkyl groups and other carbon skeletons
  • Binding role of heterocycles
39
Q

What bonds are alcohols and phenols involved in?

A
  • Hydrogen bonds. O can act as an HBA and HBD.
40
Q

What are suitable analoges for alcohols and phenols and what can they be used to test?

A

Methyl ether: OMe
- blocks HBD since there is no hydrogen present.
- Sterically blocks/limits HBA

Ester analogue: ROOH
- Blocks HBD since no hydrogen
- Sterically blocks HBA
- Electronic properties are different for an ester compared to an alcohol. The carbonyl group has a pull on the electrons making resulting in a positively charged oxygen, making it a bad HBA. At the same time we have a negativ charged oxygen aswell but the position is not similar to the alcohol, may not be relevant if we want to study the effect of the hydrogen bond of an alcohol.

41
Q

What are some isosteres of OH?

A

SH NH2 CH3

42
Q

What are some isostere of O?

A

S NH CH2

43
Q

What bonds are aromatic rings involved in?

A
  • VdW with flat hydrophobic regions
44
Q

What are suitable analoges for aromatic rings and what can they be used to test?

A

Cyclohexane - good for testing:

  • the importance of the planarty of aromatic rings (binding affinity to a planar surface and fitting into a narrow slot)
  • The importance of induced dipole interactions that aromatic rings can have with ammonium ions or pi-pi interaction between two aromatic rings.
45
Q

What bonds are alkenes involved in?

A
  • VdW with planar hydrophobic regions
46
Q

What are suitable analoges for alkenes and what can they be used to test?

A
  • Saturated alkenes (alkyls) to test the importance of planarity of the alkenes
47
Q

What bonds are ketones and aldehydes involved in?

A
  • Ketones are planar and can interact in HBA and dipole dipole interactions.
  • Aldehydes are reactive and susceptible to metabolix oxidation (to carboxylic acids) and not very relevant for drugs
48
Q

What are suitable analoges for ketones and what can they be used to test?

A
  • Alcohols to test the importance of HBA since alcohol is not as good at accepting hydrogen as a carboxyl group is. The alcohol will change the planarity aswell an limit dipole-dipole interactions both in magnitude and orientation.
  • Metyl-Ether or ester can be used as analogues to rule out HBA of the oxygen.
49
Q

What bonds are amines(NH3, NH2, NH, aromatic amines) involved in?

A
  • Hydrogen bonding both as HBA and HBD
  • Primary and secondary amines have NH-groups that can act as HBD.
  • Aromatic and heteroaromatic amines act only as HBD because the lone pair interacts with the ring structure.
  • Amines are often ionized (protonated) and can’t act as an HBA but keep their HBD abillty that even can be stronger!
  • Ionized amine can interact via ionic bonds strongly with carboxylate ion.
50
Q

What are suitable analoges for amines and what can they be used to test?

A
  • Amide analogues, that prevents HBA of amine aswell as ionic interactions (the amide group as a whole is neutral even though resonanze structure results in a positively charge)
  • Teritary amide lacks accesible hydrogens and blocks HBD activity to see if that is important for the binding of the compound. Secondary amide sterically blocks HBD
51
Q

What bonds are amides involved in?

A
  • Hydrogen bonds both HBD and HBA.
    Only the carbonyl group is present in HBA since the nitrogen lone pair interacts with the carbonyl group.
52
Q

What are suitable analoges for amides and what can they be used to test?

A
  • Many, see book
  • bevare of ketones since they are not planar!
53
Q

What bonds are quaternary ammonium salts (NR3 +) involved in?

A
  • ionized so they can interact via ionic interactions and induced dipole interactions with aromatic rings in the binding site.
54
Q

What are suitable analoges for quaternary ammonium salts and what can they be used to test?

A
  • Teritary amide group replacing the quaternary ammonium group. This tests all the ionic interactions.
55
Q

What bonds are carboxylic acids involved in?

A
  • HBA or HBD
  • If it exists as a carboxylate ion it can form ionic bonds or strong hydrogen bonds
56
Q

What are suitable analoges for carboxylic acids and what can they be used to test?

A
  • esters, primary amides, primary alcohols, ketones used to test the importance of ionic interactions since they can’t be ionized.
  • Alcohols - test if the carboyl oxygen is involved in H-bonding
  • Esters and keton - test if the hydroxyl group is involved in H-bondings
57
Q

What bonds esters involved in?

A
  • HBA
  • Susecptible to hydrolysis in vivo by esterase. Esters can be used to mask a polar functional group
58
Q

What are suitable analoges for esters and what can they be used to test?

A
  • Equivalent ether to test the importance of the carbonyl group
59
Q

What bonds phosphates, phosphonates and phosphinates involved in?

A
  • ionic interactions
  • HBA
  • phosphophate is easyly hydrolysed, makes them bad drugs
  • Phosphonate is more stable and can be monoionized can mimic the binding interactions of a phosphate group.

KOKN01 - Medicinal chemistry (12 decks)

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