D9 presentation

D.9 Drug Design
By: Sam,
Rob, and
Farah

1

D.9.1 Discuss the use of a compound library in drug
design.

• A compound library is a collection of stored chemicals, typically used
in drug discovery high-throughput screening and industrial
manufacturing.
• Each chemical has all of its chemical information like its chemical
structure, chemical properties, and physical properties, stored in a
database.
• If a pharmaceutical chemist is in need of a chemical to perform a
particular function, he or she can search the electronic compound
library database.
• This eliminates the synthesizing and the individual evaluation in the
laboratory of a large number of related compounds. Large numbers of
related compounds can be created quickly.
• This approach saves money and time.

D.9.2 Explain the use of combinatorial and parallel
chemistry to synthesize new drugs.

• Combinatorial Chemistry
• Combinatorial chemistry involves the rapid synthesis
or computer simulation of a large number of different
but structurally related molecules or materials.
• Used to synthesize a large number of different
compounds.
• Produces an electronic database or combinatorial
library.
• Used to mass produce drugs by two solid-phase
synthesis.


Solid-Phase Synthesis
• Starting material is covalently bonded to small polystyrene
beads
• The beads are reacted with one another and then split and
reacted with new substances to make new combination of
molecules
• Produced a wide range of molecules
• The products are then purified by filtering of the beads and
washing
• Used to build proteins (polypeptides)
• This method is fully automated and uses robotics


• Sets of individual compounds are then prepared
simultaneously by reacting with a number of different reagents
in arrays of physically separate reaction vessels or micro-
compartments w/o interchange of intermediates during the
assembly process
• This allows a smaller, more focused library than that obtained
with comb. chemistry
• First step towards producing larger yields of materials
identified from screening tests
• They can then be fully characterized w/o need for huge and
laborious identification procedures


Parallel Synthesis
• Used to produce smaller, more focused compound
libraries
• An alternative technique to complement combinatorial
chemistry
• Still uses solid-phase chemistry but on a larger scale
than comb. chemistry
• Advantage: all intermediates and products are generated
separately
• Involves a synthesis of a highly reactive intermediates

D.9.3 Describe how computers are used in Drug
Design

• It would be impossible to test millions of molecules in a
lab against any given target, but the computerized
screening process helps in designating a small set of
molecules that can then be tested in a wet lab.
• “In-Silico Drug Design” is a series of methods in
which the computer assists in the identification and
development of medicine and drugs. There are several
methods, each with a different purpose/ application

Design

They include:
 Molecular Docking and Virtual Screening: the ability to predict binding
conformations and affinities of millions of molecules without the need of
a single synthetic step
 Molecular Dynamics: the prediction of the evolution of molecular
systems over time, the study of protein conformation, protein-protein
interactions, the simulation of biological membranes.
 Quantum Mechanics: the study of chemical reactions, the effects of
substitutions on electronic properties and reactivity of molecules
 QSAR: Quantitative structure-activity relationship. The ability of
predicting biological properties of molecules without even the need of
knowing their target
 Homology Modeling: predicting the structures of proteins that has not
been yet crystallized

Design

• One example is the
CSIR Bio-Suite
• The Indian CSIR
(Council for
Scientific and
Industrial Research)
developed the “Bio-
Suite”
• a software tool to aid
in the drug discovery
process.

D.9.4. Discuss how the polarity of a molecule can be
modified to increase its aqueous solubility and how this
facilitates its distribution around the body

• Most medicines/drugs are fairly complex organic
molecules with low polarity.
• Tend to be insoluble in water and other polar
environments in the body, which greatly limits their
capacity as a medicine.
• To increase solubility, they can be administered as an
ionic salt.


• If the molecule
contains amines, then
they can be converted
into their hydrochloride
acid
• This can be seen in the
reaction of ammonia
and hydrochloric acid.


• An example of such a
drug is Fluoxetine
Hydrochloride, more
commonly known as
Prozac
• The opiates contain an
amine group and can
therefore be administered
as their hydrochloride salt.


• Another example is
Diamorphine (Heroine)
• The white powder is
actually Diacetylmorphine
hydrochloride, making it
soluble and possible to
inject into the body.


• The same concept applies to drugs
that contain a carboxylic acid
group. These drugs can be made
polar by converting them into
their anion and administering
them as a sodium or calcium salt.
• Take soluble aspirin for example.
The anion of aspirin enters the
body and returns to its unionized
form once it has reached a strong
acidic part of the body (the
stomach)

D.9.5 Describe the use of chiral auxiliaries to form the
desired enantiomer.

• Traditionally, the synthesis of an optically active compound normally
produces a racemic mixture of the two enantiomers. The mixture has to
be separated into the two isomers.
• Recently, a technique using chiral auxiliaries has made it possible to
synthesize just the desired isomer.
• A chiral auxiliary is an optically active chemical compound or unit that
is temporarily incorporated into organic synthesis so that it can be
carried out asymmetrically with the selective formation of one of two
enantiomers.
• This is useful as enantiomers have identical chemical properties in
relation to non-chiral reagents and cannot therefore be easily chemically
separated.
• However, because of the different properties of enantiomers in
biochemical reactions, separation is vital.

desired enantiomer.

• The chiral auxiliary attaches 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 (recycled) to leave the desired enantiomer.

desired enantiomer.

• Taxol is an anti-
cancer drug that is
synthesized using
chiral auxiliaries.

17

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