Download Option D9 Drug Design HL

Assessment Statements
 D.9.1 Discuss the use of a compound library in
drug design.
 Traditionally, a large collection of related
compounds are synthesized individually
andevaluated for biological properties. This
approach is time-consuming and expensive.
How Drugs Used To Be Discovered
 Trial and error
 Rational drug design- The action of designing
drugs to specifically counter a target molecule in
the body
 Using existing knowledge about chemistry to find
active compounds that may be useful
 Compound Libraries- Databases of compounds and
related molecules (such as those with altered
functional groups and geometries) kept by
pharmaceutical companies. These are used to
identify potential drugs that are similar to the
lead compound but with greater potency and
lesser side effects. Improves the efficiency of
finding new drugs
Compound Libraries
 electronic databases
 contain molecules which have been isolated or
synthesized and tested by pharmaceutical
companies for possible pharmaceutical properties
 information on compound:
 name, structure, 3D image, properties, biological
activity, …
 pharmaceutical companies use such libraries to
identify ‘lead’ compound for a particular ‘target’
molecule such as an enzyme, DNA or a receptor.
Solid Phase Library
In 1991s, Houghten & Lam: synthesis of a huge peptide library
20 amino acids
Solid-phase synthesis
202 = 400 dipeptides
DNA: fully automatic (solution)
peptide
203 = 8000 tripeptides
204 = 160,000 tetrapeptides
carbohydrate
small molecule (drug-like)
ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by solid
phase synthesis
Assessment Statements
 D.9.2 Explain the use of combinatorial and parallel
chemistry to synthesize new drugs.
[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.]
What is Combinatorial Chemistry?
 Is an approach that provides efficient synthesis of
a large collection of molecules.
 Screening of libraries of related compounds to
isolate the molecule of desirable property.
 Used in both academia and industries to generate
huge libraries of compounds that have important
biological properties
Combinatorial Chemistry
 Drug companies have developed libraries of compounds
which have been screened for drug activity.
 With a given core molecule or pharmacore, and a large
number of substituents, researchers use computers to
enumerate a large number of structural possibilities.
 This virtual library may consist of thousands, or even
millions of 'virtual' compounds.
 Researchers select a subset of the 'virtual library' for
actual synthesis, based upon various calculations and
criteria.
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 Much of this process is still time consuming and is
usually done by computers automated machinery
and robots.
Combinatorial Chemistry
 An example of a
pharmacore and
a reactant
system.
 By examining
multiple
possibilities
pharmaceutical
chemists can
evaluate the
medical efficacy
of various
molecules for
medicinal value.
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Combinatorial Chemistry and Solid-Phase
 The process was originally developed for polypeptide
synthesis with amino acids.
 The starting material or pharmacore is covalently
bonded to small polystyrene resin beads.
 The beads are reacted with various groups in
successive steps.
 The beads are separated from the reaction mixture
and then undergo preliminary screening for drug
activity.
 This is usually done by measuring how the substance
affects enzymes or how it may bind to receptor
cells.
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Solid Phase Chemistry
 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
 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.
Advantage of Solid-Phase
 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.
Combinatorial Chemistry
A combinatorial scheme for amino acids
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Parallel Synthesis
 Alternative to combinatorial approach,
 Solid state organic.
 Preparation of a highly reactive intermediate.
 Preparation of individual compounds simultaneously with
various reagents in separate microcells without mixing
intermediates during synthesis.
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Parallel Synthesis
 On a teflon reaction block
 Large number of wells
 Add different parts at each step
 Common conditions
12-well reaction block
Add Scaffold to each well
S
S
S
S
S
S
S
S
S
S
S
S
Wells after Addition of first
reagent
SA
SB
SC
SD
SA
SB
SC
SD
SA
SB
SC
SD
There are now twelve different
products
SA1
SB1
SC1
SD1
SA2
SB2
SC2
SD2
SA3
SB3
SC3
SD3
Similarities
Differences
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.
Synthesis of New Drugs
 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.
Assessment Statement
 D.9.3 Describe how computers are used in drug
design.
[Three-dimensional models of drugs can be created
in silico and molecular modelling software can be
used for the virtual development and evaluation of
new drugs.]
Use of Computers in Drug Design
 Used in development and evaluation of drugs
 making/using combinatorial libraries
 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.
Use of Computers in Drug Design
 Evaluation of (biological/pharmaceutical) effects
of new drugs; if the structure of a new molecule
is known or …
 If the structure is changed a 3D model can be
made and used to test its effectiveness in binding
onto a target molecule
Computer Aided Drug Design
Assessment Statement
 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.
 [Students should be aware of the ability of acidic
(carboxylic acid) and basic (amine) groups to form
ionic salts, for example, soluble aspirin and
luoxetine hydrochloride (ProzacR).]
Drug Polarity Modifications
 Many compounds that are of pharmacological importance
are large complex organic molecules that are not very polar
 They are largely insoluble in water. Their ionic salts, either
as sodium salts or hydrochloride salts are used to make
them more soluble.
Aspirin or acetyl
salicyclic acid is
converted to the
sodium salt.
Sertraline is an amine
compound that is
converted to a
hydrochloride salt to
make it more soluble.
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Solubility and Uptake
 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.
Improving Solubility
 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.
 Examples: aspirin (acid) and fluoxetine (amine)
Aspirin
 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
Aspirin
C6H4(OCOCH3)COOH + NaOH → C6H4(OCOCH3)COONa + H2O
Fluoxetine
 Fluoxetine hydrochloride (Prozac®), an ionic salt,
is produced by reacting a strong acid such as
hydrochloric acid with the secondary amine group
in fluoxetine.
 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.
Fluoxetine to fluoxetine
hydrochloride
Assessment Statement
 D.9.5 Describe the use of chiral auxiliaries to
form the desired enantiomer.
 [A chiral auxiliary is used to convert a non-chiral molecule into
just the desired enantiomer, thus avoiding the need to separate
enantiomers from a racemic 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 (recycled) to leave the desired enantiomer. An
example is the synthesis of Taxol, an anti-cancer drug.]
Chiral Auxillaries
 Traditional synthesis of optically active compounds
results in a racemic mixture with equal amounts of each
enantiomer.
 Only one of the enantiomers has pharmacological value.
(i.e. thalidomide).
 Separating enantiomers from racemic mixtures is often
difficult and complicated.
 The use of chiral auxilliaries makes it possible to
synthesize only one of the two enantiomers.
 A chiral auxilliary is a chiral molecule that is attached
to the starting material during a synthesis that creates
the appropriate stereo-chemical environment so that
only one enantiomer is produced.
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Chiral Auxiliary
 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.
 Iit 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.
Asymmetric Synthesis
Synthesis of One Enantiomer using a Chiral Auxiliary
O
O
O
chemical steps
OH
NH
2
OH
Put auxiliary on
OH
NH
2
Bothhandedforms of product
(racemic mixture; 1:1mixtureof enantiomers)
O
O
chemical steps
O
takeauxiliary off
OH
NH
2
NH
2
O
[
HN
Chiral Auxiliary
:
O
]
Synthesis with Chiral Auxilliaries
A chiral auxiliary is a molecule that is temporarily incorporated
into an organic synthesis. Its asymmetry allows the formation of
a chiral intermediate followed by selective formation of one of
two stereoisomers depending on the reagent and/or reaction
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conditions.
Taxol
 The anti-cancer drug TAXOL is found in the Pacific
Yew tree, but there is not a sufficient supply to meet
demand.
 SinceTaxol is a very chiral molecule, one possibility
is to make it synthetically.
 The potential synthesis is very complicated and
would require using several chiral auxilliaries..
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