medicines drug design D9

Report
Drug design
electronic databases
 contain molecules which have been isolated or
synthesized and tested by pharmaceutical
companies for possible pharmaceutical properties
 information on compound:
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 name, structure, 3D image, properties, biological
activity, …
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pharmaceutical companies use such libraries to
identify ‘lead’ compound for a particular ‘target’
molecule such as an enzyme, DNA or a receptor.
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From IB syllabus:
 Traditionally, a large collection of related
compounds are synthesized individually and
evaluated for biological properties. This approach is
time-consuming and expensive.
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involves simultaneous chemical synthesis
different but structurally related compounds
(all possible combinations) from a small
number of reactant molecules which are
reacted with a variety of reactants,
uses mix-and-split technique and resin beads
screen each product for its biological activity,
resulting in a “combinatorial library”.
all is automated and uses computers/robots
A technique used in combinatorial
chemistry
 synthesizes large volume of compounds
 reactions take place on the surface of
resin beads
 each type of reactant molecule is
bonded covalently onto a very small
resin bead
 uses mix and split process
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The different reactants are mixed and then split
into separate portions i.e. each portion has all
reactants
To each portion a different reactant is added and
a reaction is allowed to occur
The separate portions are then mixed again
after which they are split into separate portion
To each portion a different reactant is added
again…
This is repeated.
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When synthesis reactions are complete, the
products are removed easily from the beads
by filtering off the beads and washing them.
After that the products are tested “in vitro”
and “in vivo” to find out their biological
activity.
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Parallel chemistry or parallel synthesis involves the
synthesis of a smaller but selected group of
compounds with a different compound in each
reaction vessels. In most combinatorial techniques
the compounds are mixed and need to be
separated; not necessary in parallel synthesis as
multiple experiments run in parallel.
Combinatorial synthesis
•Generates large, more
diverse libraries “combinatorial library”.
•Produces a ‘mixture’ of
compounds in same
reaction vessel. Uses
mix/split method
Parallel synthesis
•Small focused libraries
•Produces a ‘single’
product in each/different
reaction vessel.
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IB Syllabus says:
 Combinatorial chemistry is used to synthesize a
large number of different compounds and screen
them for biological activity, resulting in a
“combinatorial library”. Alternatively, parallel
synthesis can produce smaller, more focused
libraries. Students should be aware of the
importance of solid-phase chemistry.
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Used in development and evaluation of drugs
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making/using combinatorial libraries
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3D modeling software can be used to show
interaction between medicine and active site
on target molecule/receptor without actually
making the medicine. This also allows the
design of molecules with the perfect fit and
then attempt to chemically produce them.
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evaluation of (biological/pharmaceutical)
effects of new drugs; if the structure of a new
molecule is known or …
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If the structure is changed a 3D model can be
made and used to test its effectiveness in
binding onto a target molecule
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many medicines are either non-polar or
relatively non-polar molecules.
If their target area in the body is in an
aqueous environment their low solubility in
water, as a result of their non-polarity, will
make their uptake slow
it will take time for the medicine, after
administration, to reach its target molecule.
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In the case of non-polar molecules with
either acidic (carboxylic acid) or basic (amine)
groups the polarity can be increased by
converting them into ionic salts by adding
either alkalis or acids.
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Examples: aspirin (acid) and fluoxetine
(amine)
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Aspirin was derived from 2-hydroxybenzoic
acid by esterification, next step…
Aspirin which is insoluble in water and which
has a carboxylic acid group can be made into
an ionic salt by reacting it with a strong alkali
such sodium hydroxide to form a soluble
sodium salt as shown by the equation below:
C6H4(OCOCH3)COOH + NaOH → C6H4(OCOCH3)COONa + H2O
C6H4(OCOCH3)COOH + NaOH → C6H4(OCOCH3)COONa + H2O
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fluoxetine hydrochloride (Prozac®), an ionic
salt, is produced by reacting a strong acid
such as hydrochloric acid with the secondary
amine group in fluoxetine.
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the nitrogen atom in the secondary amine
donates its non-bonding pair to the hydrogen
ion forming a basic cation to which the
chloride ion is attracted.
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If enantiomers in a racemate have different
physiological activities it is necessary to
isolate the desired enantiomer from the
mixture.
However, this is a wasteful process and it is
therefore better to synthesize directly the
desired enantiomer by preventing the
synthesis of the other enantiomer. This can
be achieved by using a chiral auxiliary.
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a chiral auxiliary is an enantiomer itself
used to convert a non-chiral reacting molecule
into just one enantiomer i.e. the enantiomer with
the desired pharmaceutical effect.
it does that by attaching itself to the non-chiral
molecule to create the stereochemical conditions
necessary to force the reaction to follow a certain
path i.e. the production of the desired enantiomer
and not the other enantiomer.
once the new desired molecule has been formed,
the auxiliary can be taken off and recycled.

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