D9 Drug design
 Compound libraries
 Combinatorial and parallel chemistry
 The use of computers
 Modifications for polarity
 Chiral synthesis
How are drugs found?
 Plants and fungi have healing properties, e.g. willow tree
bark and poppy seeds
 The active substance in the specimen
is purified and it’s structure analysed (salicylic acid
and morphine)
 A large collection of related compounds are synthesized
individually and evaluated for biological properties- time
consuming and expensive (aspirin and heroin)
 Substances can also be accidentally found (penicillin),
the analogues are synthesized
The use of compound libraries in drug
design
 A chemical library or compound library - a collection
of stored chemicals
 Used for scientific experimentation or industrial
manufacture
 For each chemical there is information stored such
as the chemical structure and physiochemical
characteristics (melting point, polarity, reactivity)
Combinatorial and parallel chemistry
 Used to synthesize a large number of different
compounds and screen them for biological activity
 Result in a “combinatorial library”
 Combinatorial chemistry involves the rapid synthesis
or the computer simulation of a large number of
different but structurally related molecules or
materials
Parallell chemistry
Solid-phase organic synthesis
 For eg protein synthesis
 The starting amino acid is covalently bound to very
small beads of polystyren
 Amino acids are the coupled to the first one by a
process known as mix and
split
 For 3 aminoacids nine
possible dipeptides can
be formed, etc.
3 amino acids, X, Y and Z
By using large amounts of the second and subsequent
Amino acids the reactions can be made with high yields
Solid-phase organic synthesis, cont.
 The resulting peptides can be easily purified by fi
ltering off the beads and washing
 Has been extended tp other types of molecules, eg
benzodiazepines
 Once a particular substance
has been identified it can be
synthesized in a lager scale
D9.2 Explain the use of combinatorial and
parallel chemistry to synthesize new
drugs
 Combinatorial chemistry has probably had its biggest
impact in the pharmaceutical industry. Researchers
attempting to optimize the activity profile of a compound
create a 'library' of many different but related compounds
 Parallel synthesis can produce smaller, more focused
libraries and has certain advantages over combinatorial
chemistry in that all intermediates and products are
generated separately and in sufficient amounts for full
characterization and biological screening, without the
need for long identification procedures.
The use of molecular modelling in drug
design
 Three-dimensional models of drugs can be created
using computer simulation and molecular modeling
software can be used for the virtual development
and evaluation of new drugs
 Useful in combinatorial chemistry
How to modify the polarity of a molecule to increase its
aqueous solubility ?
 Acidic (carboxylic acid) groups have the ability to
form ionic salts
 Aspirin
+ NaOH
Hydrogen bondingrelatively weak
Moderately water soluble
Ionic bonding
relatively strongWater soluble
How to modify the polarity of a molecule to increase its
aqueous solubility, cont.
 Basic (amine) groups have the ability to form ionic
salts
 Fluoxetine hydrochloride (Prozac®).
+ HCl
Hydrogen bonding but mostly van der Waal
– weak, unpolar
Not water soluble
… turn it into a salt!
 Drugs with carboxylic groups can be reacted with
sodium (or potassium) hydroxide to be made into a
salt
 Drugs with amine groups can be reacted with
hydrogen chloride to be made into a salt- a
hydrochloride
Chiral synthesis- how to make the
enantiomer you want and to avoid the other
 Start with chiral molecule (eg glucose)
 Use chiral auxiliary*
 Chiral catalyst
 Separate the mixture on a chiral column
Definition of chiral auxiliary
 A chiral auxiliary is a chemical compound or unit that
is temporarily incorporated into an organic synthesis
so that it can be carried out asymmetrically with the
selective formation of one of two enantiomers
The use of chiral auxiliaries
 A chiral auxiliary is used in the synthesis to convert a
non-chiral molecule into the desired enantiomer, thus
avoiding the need to separate enantiomers from a
mixture
 It works by attaching itself to the non-chiral molecule
to create the stereochemical conditions necessary to
force the reaction to follow a certain path. Once the
new molecule has been formed, the auxiliary can be
taken off to leave the desired enantiomer
Synthesis with chiral auxilary (the molecule in blue)
ee-enantiomeric excess
Chiral auxiliaries are used for the
synthesis of Taxol, an anti-cancer drug
Taxol (Paclitaxel)