D9 – Drug Design
(HL)
D.9.1 Discuss the use of a compound
library in drug design
 Over the years, molecules of various substances
have been isolated or synthesized, and tested for
their pharmacological properties.
 These form a “compound library”, as compounds
from these libraries can be utilized to make changes
to the structure to produce similar drugs.
 It used to be that this was a time consuming process,
until…..
D.9.2 Explain the use of combinatorial and
parallel chemistry to synthesize new drugs.
Combi-Chem!!!
 Ahhh, combinatorial chemistry…much better.
 Thousands of possible compounds are tested to
research the biological activity of each.
 Computer-controlled syringes carry out
repetitive chemical techniques.
 Parallel synthesis can produce smaller, focused
libraries by using robotics to carry out identical
chemical processes such as adding fixed
volumes of substances.
D.9.2 Explain the use of combinatorial and
parallel chemistry to synthesize new drugs.
 An example of parallel synthesis is eight different
carboxylic acids can be reacted with eight different
alcohols.
 Question: What functional group is created, and how
many different compounds can be formed?
 A: Esters are formed and 64 (8x8) different
combinations can be formed.
D.9.2 Explain the use of combinatorial and
parallel chemistry to synthesize new drugs.
 Solid-phase synthesis uses very small resin
beads (100 µm in diameter) to covalently
bonded starting materials.
 For example, compound X, Y and Z are all
covalently bonded onto resin beads. They are
then mixed together to react. How many
different combinations do you have (counting
the resin bead)?
 A: 3x3=9
D.9.2 Explain the use of combinatorial and
parallel chemistry to synthesize new drugs.
 Now you have nine different combinations
(● X-X ●X-Y, ●Y-X, etc.). You split the compounds
up, and react them again with X, Y, and Z. How many
combinations do you now have?
A: 27
What if you reacted a third time?
B: 81
These combinations are tested to see how they affect
enzymes and bind to receptor cells. This information
is used to build combinatorial libraries.
D.9.3 Describe how computers are
used in drug design.
 Molecular modelling software allows scientist to
build 3-D representations of molecules and mimic
their molecular behavior.
D.9.4 Discuss how the polarity of a molecule can be
modified to increase its aqueous solubility and how this
facilitates distribution around the body.
 Take a look at salicylic acid and it’s polarity (and
ability to donate hydrogen ions), and compare it
to acetylsalicylic acid in your data booklet:
Because of it’s acidity, it would
damage the esophagus and stomach, so
it needed to be chemically modified.
Initially it was reacted with sodium
hydroxide to create sodium
salicylate—a soluble salt of salicylic
acid
D.9.4 Discuss how the polarity of a molecule can be
modified to increase its aqueous solubility and how this
facilitates distribution around the body.
 However, this was bitter tasting and still irritating to
the stomach lining. So aspirin was developed by
creating an ester to make it less acidic, and therefore
less irritating. It is also tasteless.
 However, this form is also insoluble in water. So the
salt of acetylsalicylic acid can also be purchased.
 The more insoluble a substance is, the longer it takes to
dissolve. The longer it takes, the less effective it is.
D.9.4 Discuss how the polarity of a molecule can be
modified to increase its aqueous solubility and how this
facilitates distribution around the body.
 Basic molecules can also be turned into a salt by
adding hydrochloric acid.
 For example, Prozac® can be made into
fluoxetine hydrochloride. This makes it water
soluble.
D.9.5 Describe the use of chiral auxillaries
to form the desired enantiomer.
 As you know, different enantiomers can have different
biological effects.
 A chiral auxillary attaches to a non-chiral compound to
be synthesized, so only the desired enantiomer is
created.
 Due to steric hindrance, the auxillary directs the
“attacking molecule” to attack from only one side.
 The auxillary can be removed and then re-used.
 This process is used when synthesizing Taxol.