Drug Design and Toxicity Flashcards
what does pharmacophore define?
the important groups involved in binding and their relative positions
what types of molecules is conformational analysis difficult in and what do we do to compare their activity?
- simple flexible molecules with a large number of conformations
- we look at the activity of their rigid analogues
how do we predict pharmacophores of drug molecules?
use their target sites of interactions to predict the key interactions they make
what is the simplification concept?
- 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.
what are the main issues with the simplification concept?
- oversimplification may cause decreased activity and selectivity
- simpler molecules have more conformations
- more likely to interact with more than one target binding site
why do we rigidify structures?
to limit conformations (conformational restraint)
- increases activity
- increases selectivity
what is the issue with simple and flexible compounds?
they fit several targets due to different active conformations therefore they’re less selective
what is the issue with complex compounds?
may be more difficult to synthesise
how can we rigidify a structure?
- by rotating a bond
- by preventing bond rotation (e.g. by adding extra bonds)
What must we ensure if we change the conformation of a drug molecule to prevent bond rotation?
-make sure the activity of the drug is retained
in long chain molecules, what can we do to increase/maintain activity and cause a conformational restraint?
add more bonds to lock the bonds (e.g. double/triple bonds, or adding a methyl group)
why must drugs be polar?
- to be soluble in aqueous conditions
* to interact with molecular targets
why must drugs be fatty?
- to cross cell membranes
* to avoid rapid excretion
what 2 characteristics must drugs have?
hydrophilic and lipophilic
how can we vary the hydropilic/hydrophobic balance of a structure?
Varying the size of alkyl groups
larger alkyl groups = increased hydrophobicity
what is the disadvantage of varying alkyl group sizes on a molecule?
May interfere with target binding for steric reasons
why do we mask/remove polar groups?
decreases polarity and increases hydrophobic character
what is the disadvantages of masking/removing polar groups?
• Polar group may be involved in target binding
• Unnecessary polar groups are likely to have been removed already
(simplification strategy
what is the effect of adding polar groups to a molecule and what is its usefulness?
- increases polarity and decreases hydrophobic character
* Useful for targeting drugs vs. gut infections, i.e. reduce gut absorption
what is the effect of modifying pKa?
alters percentage of drug which is ionised
why are ionised drug poorly absorbed?
they’re too water soluble
how can we modify the pKa of an amine?
modify the alkyl substituent on the amine nitrogen
how can we modify the pKa of aromatic amines?
vary the aryl substituents (electron withdrawing groups makes the amine less basic)
what do bulky groups do to the molecule in metabolic stability?
they act as a shield (e.g. protecting a susceptible group from hydrolysis, and hindering attack by nucleophiles or enzymes)
describe electronic stability?
-process of stabilising labile functional groups (e.g. esters) by pushing in electrons
what is used to feed electrons into carbonyl groups and how does this affect its reactivity and stability?
- nitrogen
- makes it less reactive
- makes it more chemically and metabolically stable
how can you increase the stability of ester containing compounds?
replace the labile ester with more stable urethane or amide
what effect does stereoelectronic stability have on chemical and metabolic stability?
increases them both
what are isosteres?
variation of the structural characteristics (functional groups) in a rational manner.
-they have similar size, shape and electronic properties
what is the rationale of bioisosteres?
- replacing susceptible groups with a different group without affecting activity
- should improve pharmacokinetic properties
- can look quite different as not necessarily isosteres
what is metabolism blocking and what effect does this have?
- introducing groups at a susceptible site to block metabolism
- this increases metabolic stability and drug lifetime
what effect does replacing labile groups have?
reduces the drug’s susceptibility to metabolism making it more metabolically stable
why do we move the metabolic target group on a drug molecule?
- 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
what are pro-drugs?
Inactive compounds that are converted to active compounds in the body
• Often this is a metabolic event
• Can be a mechanistic event
what are pro-drugs used for?
- Improving membrane permeability
- Prolonging activity
- Masking toxicity and side effects
- Varying water solubility
- Drug targeting
- Improving chemical stability
what are esters used for?
- to mask polar and ionisable carboxylic acids
- to improve the permeability of the compound
where are esters hydrolysed and by what?
- hydrolysed in blood
- by esterases
when do we use esters to mask carboxylic acids?
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).
in aspirin, why is the phenol group masked by an ester?
to reduce toxicity caused by OH group which causes stomach ulcers.
what is the rationale behind anti-drugs?
- decreases metabolic stability and drug lifetime
- reduces drug life-time in the body hence reduced side effects
