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)
