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Pharmacy Stage 2 > Drug Design and Toxicity > Flashcards

Drug Design and Toxicity Flashcards

1
Q

what does pharmacophore define?

A

the important groups involved in binding and their relative positions

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2
Q

what types of molecules is conformational analysis difficult in and what do we do to compare their activity?

A
  • simple flexible molecules with a large number of conformations
  • we look at the activity of their rigid analogues
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3
Q

how do we predict pharmacophores of drug molecules?

A

use their target sites of interactions to predict the key interactions they make

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4
Q

what is the simplification concept?

A
  • Lead compounds from natural sources are often complex and difficult to synthesise
  • If we simplify them, synthesis of their analogues will be easier, quicker and cheaper
  • simpler structures may fit binding site easier and increase activity
  • they may also be more selective hence less toxic if excess functional groups are removed.
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5
Q

what are the main issues with the simplification concept?

A
  • oversimplification may cause decreased activity and selectivity
  • simpler molecules have more conformations
  • more likely to interact with more than one target binding site
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6
Q

why do we rigidify structures?

A

to limit conformations (conformational restraint)

  • increases activity
  • increases selectivity
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7
Q

what is the issue with simple and flexible compounds?

A

they fit several targets due to different active conformations therefore they’re less selective

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8
Q

what is the issue with complex compounds?

A

may be more difficult to synthesise

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9
Q

how can we rigidify a structure?

A
  • by rotating a bond

- by preventing bond rotation (e.g. by adding extra bonds)

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10
Q

What must we ensure if we change the conformation of a drug molecule to prevent bond rotation?

A

-make sure the activity of the drug is retained

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11
Q

in long chain molecules, what can we do to increase/maintain activity and cause a conformational restraint?

A

add more bonds to lock the bonds (e.g. double/triple bonds, or adding a methyl group)

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12
Q

why must drugs be polar?

A
  • to be soluble in aqueous conditions

* to interact with molecular targets

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13
Q

why must drugs be fatty?

A
  • to cross cell membranes

* to avoid rapid excretion

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14
Q

what 2 characteristics must drugs have?

A

hydrophilic and lipophilic

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15
Q

how can we vary the hydropilic/hydrophobic balance of a structure?

A

Varying the size of alkyl groups

larger alkyl groups = increased hydrophobicity

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16
Q

what is the disadvantage of varying alkyl group sizes on a molecule?

A

May interfere with target binding for steric reasons

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17
Q

why do we mask/remove polar groups?

A

decreases polarity and increases hydrophobic character

18
Q

what is the disadvantages of masking/removing polar groups?

A

• Polar group may be involved in target binding
• Unnecessary polar groups are likely to have been removed already
(simplification strategy

19
Q

what is the effect of adding polar groups to a molecule and what is its usefulness?

A
  • increases polarity and decreases hydrophobic character

* Useful for targeting drugs vs. gut infections, i.e. reduce gut absorption

20
Q

what is the effect of modifying pKa?

A

alters percentage of drug which is ionised

21
Q

why are ionised drug poorly absorbed?

A

they’re too water soluble

22
Q

how can we modify the pKa of an amine?

A

modify the alkyl substituent on the amine nitrogen

23
Q

how can we modify the pKa of aromatic amines?

A

vary the aryl substituents (electron withdrawing groups makes the amine less basic)

24
Q

what do bulky groups do to the molecule in metabolic stability?

A

they act as a shield (e.g. protecting a susceptible group from hydrolysis, and hindering attack by nucleophiles or enzymes)

25
Q

describe electronic stability?

A

-process of stabilising labile functional groups (e.g. esters) by pushing in electrons

26
Q

what is used to feed electrons into carbonyl groups and how does this affect its reactivity and stability?

A
  • nitrogen
  • makes it less reactive
  • makes it more chemically and metabolically stable
27
Q

how can you increase the stability of ester containing compounds?

A

replace the labile ester with more stable urethane or amide

28
Q

what effect does stereoelectronic stability have on chemical and metabolic stability?

A

increases them both

29
Q

what are isosteres?

A

variation of the structural characteristics (functional groups) in a rational manner.
-they have similar size, shape and electronic properties

30
Q

what is the rationale of bioisosteres?

A
  • replacing susceptible groups with a different group without affecting activity
  • should improve pharmacokinetic properties
  • can look quite different as not necessarily isosteres
31
Q

what is metabolism blocking and what effect does this have?

A
  • introducing groups at a susceptible site to block metabolism
  • this increases metabolic stability and drug lifetime
32
Q

what effect does replacing labile groups have?

A

reduces the drug’s susceptibility to metabolism making it more metabolically stable

33
Q

why do we move the metabolic target group on a drug molecule?

A
  • if the metabolically susceptible group is important for binding so the group shifts its position to make it unrecognisable by the metabolic enzyme.
  • but it will still be recognisable by the target
34
Q

what are pro-drugs?

A

Inactive compounds that are converted to active compounds in the body
• Often this is a metabolic event
• Can be a mechanistic event

35
Q

what are pro-drugs used for?

A
  • Improving membrane permeability
  • Prolonging activity
  • Masking toxicity and side effects
  • Varying water solubility
  • Drug targeting
  • Improving chemical stability
36
Q

what are esters used for?

A
  • to mask polar and ionisable carboxylic acids

- to improve the permeability of the compound

37
Q

where are esters hydrolysed and by what?

A
  • hydrolysed in blood

- by esterases

38
Q

when do we use esters to mask carboxylic acids?

A

when a carboxylic acid is required for target binding. So the ester helps the drug enter the blood, then it gets hydrolysed in the blood into a carboxylic acid and the leaving group (alcohol).

39
Q

in aspirin, why is the phenol group masked by an ester?

A

to reduce toxicity caused by OH group which causes stomach ulcers.

40
Q

what is the rationale behind anti-drugs?

A
  • decreases metabolic stability and drug lifetime

- reduces drug life-time in the body hence reduced side effects

Pharmacy Stage 2 (85 decks)

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