Download Topic guide 9.3: Drug discovery and design

Unit 9: Medicinal Chemistry
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Drug discovery and
design
Modern chemical techniques have revolutionised the process of drug design.
A knowledge of the structure of receptor sites and computer modelling
techniques to predict the binding of drug molecules to these sites means that
research is now able to identify likely candidates for new drugs before the
drug has even been synthesised by chemists. Once compounds are identified,
new combinatorial techniques allow chemists to synthesise large numbers
of structurally related molecules to enable rapid identification of the most
promising candidate for further development.
In this unit you will look at how these new techniques of computer modelling
and combinatorial chemistry are being applied in modern drug design and
development.
On successful completion of this topic you will:
•• understand the stages of drug discovery and design (LO3).
To achieve a Pass in this unit you need to show that you can:
•• discuss the issues for consideration when designing a new drug (3.1)
•• explain the concepts of structure-activity relationships with respect to
drug design (3.2)
•• explain the role of combinatorial chemistry in drug synthesis and
development (3.3).
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Unit 9: Medicinal Chemistry
1 Designing a new drug
Dr Richard Lewis is the global head of Computer-aided Drug Design at Novartis International,
a multinational pharmaceutical company based in Basel, Switzerland. He talks about the drug
discovery process and gives some examples of how the various disciplines involved in the process
interact with each other. You can read more about the chemical and biochemical aspects of the
research in sections 2 and 3 of this topic guide.
Dr Richard Lewis,
Global Head of Computeraided Drug Design at
Novartis International
‘The essential principle is that we aim to invent safe drugs for unmet medical needs. With modern
chemical and computing techniques we can make and investigate a myriad of new compounds.
There are so many avenues we could go down, but ultimately we have to take pragmatic decisions
to ensure that we can deliver a successful product in a reasonable time frame.
We need to begin by identifying a disease that is amenable to drug intervention. We will need
to know its biology – what is the pathway by which the disease operates? Are there reactions
or processes within that pathway which could be somehow disrupted? Can this disruption be
enabled by the relatively small molecules, which we will be aiming to design and develop?
Even at this stage we may need to be looking further ahead before we know whether we have a
viable project. Assuming that these theoretical studies look promising, we would need to have
some confidence that we will be able to evaluate the project at different stages – how will we
screen the molecules we develop to help identify the most promising target molecules? Will the
effects of the drugs be measurable in clinical trials? Is it likely to be technically and financially
feasible to develop this into a marketable drug?
A good example of recent research, which illustrates the principles of drug design, takes
Alzheimer’s disease as a target. Clearly the potential market for a drug that has demonstrable
efficacy in reducing symptoms or slowing the disease progression would be enormous. The target
reaction is one in which an enzyme called BACE-1 cleaves a protein known as the amyloid precursor
protein. Cleavage of this protein is known to be an important step along the route that eventually
leads to the build-up of the plaques, which are observed in the brains of Alzheimer’s patients.
Once we have identified a target reaction in this way we need to identify molecules – known as
lead compounds – which can act as ligands by bonding strongly to the binding site of the enzyme
and thereby inhibit it. The starting point for this might be the natural substrate for the enzyme, but
even screening analogues of this will be a potentially lengthy and costly process; the conventional
method for finding a ‘hit’ in this way might have been to perform high-throughput screening. In
this process, maybe as many as a million different compounds are synthesised and their ability to
act as a ligand tested by a suitable assay procedure.
In the research projects that I manage, we use computer modelling to carry out structure-based
pharmacophore screening. The detailed three-dimensional structure of the binding site is
established, using X-ray crystallography allied to NMR spectroscopy. Then computer modelling can
be used to deduce the likely structure of the pharmacophore – the part of the ligand molecule that
enables it to be recognised at the binding site. Quantitative structure-activity relationship models
can be used to predict the most effective ligands based on our knowledge of the pharmacophore
and, as a result, we can prioritise the experimental investigation of just the most likely ligands.
It is tempting to imagine that identifying an effective ligand for an enzyme such as BACE-1
might be a real breakthrough in Alzheimer’s research. In reality, however, it is just one very small
step along the way towards a treatment that may have some promise in the future. For the lead
compounds that we identify to become a drug, other research teams must find ways of adjusting
its structure to ensure that it is very specific in its inhibition of BACE-1 and that it has suitable
hydrophobic and polar properties to allow it to be absorbed, distributed, metabolised and excreted
at a suitable rate. If they achieve this then it is just possible that the drug may show some useful
efficacy in human beings.
Drug discovery involves genuine partnership across a wide range of disciplines. It is a wonderfully
varied and challenging field to work in, and one in which we know that the data we obtain today
may one day lead to a better and longer life for maybe millions of patients.’
9.3: Drug discovery and design
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Unit 9: Medicinal Chemistry
Figure 9.3.1: The three key stages
of drug discovery and design.
Target identification
●
Choosing the disease
●
Choosing a drug target
Identifying a lead compound
Identifying a screening method
●
Finding a lead compound
●
Isolating, purifying and
identifying its structure
●
Optimising the lead compound
Ensuring specificity
● Optimising rate of
absorption, metabolism, etc.
● Maximising efficacy
●
Activity
The three key stages of drug discovery and design (see Figure 9.3.1) can be described as:
1 target identification
2 identifying lead compounds by screening
3 lead optimisation.
Link
You will learn more about the
processes that Dr Lewis describes in
the presentation ‘Drug Design’.
Look at Dr Lewis’s description of the research into BACE-1 inhibitors. Explain what happened in
each of these stages.
2 Structure-activity relationships
Structure-activity relationship and drug design
Link
There are some examples of threedimensional representations of
binding sites and ligands in the
presentation ‘Drug Design’.
Key terms
Analogues: Molecules with
structural similarities to the lead
compound.
Screening: A procedure used to
predict the biological activity of a
drug or other biochemical substance.
Lead compound: A molecule with
proven biological activity that is the
starting point for a development
process to become an effective drug.
Pharmacophore: The part of
the structure of a drug molecule
responsible for its pharmacological
action. In the context of drug design
it can also mean the part of the
molecule which binds to a binding
site.
9.3: Drug discovery and design
Drug design is based on the basic premise that molecules with similar structures
will display similar activities – this principle is known as the structure-activity
relationship. If a molecule, for example, a naturally occurring metabolite, could
be shown to have some biological activity, then molecules with similar structures
might show the same (or enhanced) activity.
The traditional model of drug design involved screening these molecules by
performing in vitro assays on a range of possible drug candidates and hence
identifying one or more lead compounds that show promising levels of activity.
Lead compounds are then chemically modified to increase their effectiveness in a
process known as lead optimisation.
This process can be made more targeted by making use of structure-activity
relationships: if the three-dimensional position of functional groups in a binding
site is known, then deductions can be made about where a ligand may bind. This
is done using powerful computer software, and the use of these computational
techniques to screen molecules is often referred to as in silico screening.
Pharmacophore
A key aspect of drug design is the identification of the pharmacophore. This can
be done by examining the structural features of molecules that show activity in
the assays, but modern computing techniques allow the pharmacophore structure
to be deduced directly from the structure of the binding site.
Such modelling requires a very detailed knowledge of the three-dimensional
structure of the binding site. This is obtained by combining a range of techniques
such as X-ray crystallography and NMR spectroscopy.
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Unit 9: Medicinal Chemistry
Varying the substituents
Once the structure of the pharmacophore is established, a range of molecules with
different substituents (for example, by adding a range of groups to free hydroxyl
or amine groups in the pharmacophore).
Figure 9.3.2: A wide variety of
possible ligands can be created by
adding substituents to an identified
pharmacophore (circled).
O
N
O
O
N
H
S
O
N
H
O
O
O
O
O
N
H
O
H2N
N
H
N
H
OH
O
Link
You will find out more about how
computer-aided drug design allows
chemists to design drugs that bind
effectively to the target receptor site
in the presentation ‘Drug Design’.
Key terms
Lipophilicity: The tendency of a
molecule to dissolve in non-polar
solvents such as lipids.
Partition coefficient: The ratio of
the concentrations of a solute in two
different solvents once equilibrium
has been reached.
Hydrophilicity: The tendency of a
molecule to dissolve in water.
N
H
N
OH
OH
H
N
O
N
H
OH
O
O
N
H
O
O
N
H
OH
NH2
H
N
O
N
H
O
O
OH
O
OH
Quantitative structure-activity relationships (QSAR)
Attempting to quantify structure-activity relationships allows drug designers to
more rapidly identify likely drug molecules. While it is true that such methods
have a significant level of uncertainty attached to them, the use of quantitative
data allied to the chemists’ knowledge of the behaviour of functional groups is
providing an increasingly valuable tool.
Surprisingly, QSAR modelling techniques date from well before the era of
computer-aided drug design. Early methods involved characterising the groups
present in a potential drug molecule by parameters such as their lipophilicity.
This is measured by calculating the partition coefficient, Pi, which is calculated
by knowing the concentration of the compound in octan-1-ol and water at
equilibrium with one another:
Pi =
concentration of compound in octan-1-ol
concentration of compound in water
A high partition coefficient indicates high lipophilicity and low hydrophilicity.
The overall contribution of these parameters to the likely activity of the molecule
could then be estimated by mathematical manipulation.
Take it further
A highly detailed survey of the way in which QSAR has developed, taken from Medicinal Chemistry
and Drug Discovery, (Burger, 2003) can be found at
http://media.johnwiley.com.au/product_data/excerpt/03/04712709/0471270903.pdf.
This includes information about the different models of combining parameters and tables of
data for some of the main parameters that characterise the drug-receptor binding, for example,
hydrophobicity Pi, molar refractivity (related to the polarisability) and various steric factors.
QSAR data is frequently included in research papers and you will be able to see how the data is
used to produce an overall measure of biological activity.
9.3: Drug discovery and design
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Unit 9: Medicinal Chemistry
Checklist
At the end of this section, you should be familiar with the following ideas:
 knowledge of the structure of the binding site allows the structure of a pharmacophore to be
deduced
 structure-activity relationships can be used to predict the effect of making changes to the
pharmacophore
 quantitative structure-activity relationships are used to help design drug structures using
numerical data.
3 Combinatorial chemistry
As seen earlier, drug discovery and development requires that a large number of
molecules with structural similarities can be synthesised quickly and cheaply to
enable their activity to be assayed (screened).
This is enabled by combinatorial methods. The techniques of combinatorial
chemistry were first devised to enable polypeptide synthesis but have now been
extended for use in the synthesis of a wide range of products.
A very simple example of a combinatorial method would be the synthesis of a
range of amides (see Figure 9.3.3). In each reaction, the reaction conditions and
reaction vessels will be the same.
Figure 9.3.3: A simple example
of combinatorial chemistry. Nine
different possible products can
be formed by combining these
two combinatorial libraries.
Amine
+
Acyl chloride
Amide
R1 —NH2
R4 —COCl
R1 —NH—CO— R4
R2 —NH2
R5 —COCl
R1 —NH—CO— R5
R3 —NH2
R6 —COCl
R1 —NH—CO— R6
R2 —NH—CO— R4
Combinatorial libraries
R2 —NH—CO— R5
R2 —NH—CO— R6
R3 —NH—CO— R4
R3 —NH—CO— R5
R3 —NH—CO— R6
Products
Combinatorial libraries
Principles of synthesis
In drug synthesis, the combinatorial reaction involves a starting material that is
thought likely to have some biological activity. A range of molecules with a similar
structure is prepared to form the first combinatorial library. There will be a core
portion of the molecule common to all the members of this library, known as the
scaffold structure.
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Unit 9: Medicinal Chemistry
The second combinatorial library used in the synthesis will then consist of a range
of related reagents.
The 20 starting materials and 50 reagents would then create a potential for 1000
‘first round’ products. The synthesis can then continue with a second step to
modify the scaffold structure still further; if 50 further reagents are used then there
will be 50,000 ‘second round’ products to screen (see Figure 9.3.4).
Figure 9.3.4: The number of possible
products which can be produced by
combinatorial techniques multiplies
rapidly in multi-step syntheses.
Starting materials
20 molecules
Reagents
50 molecules
First round products
1000
Second round products
50,000 molecules
Reagents
50 molecules
Activity
Take it further
Use research to find details of
combinatorial libraries used in the
search for a specific lead compound.
Use the structures of the molecules
in each library to identify the scaffold
structure.
A full guide to the current principles of combinatorial chemistry can be found at
http://www.combichemistry.com/
Key term
Oligo-: A prefix used to denote a
small number (<50) of monomer
molecules bonded together to form
larger molecules.
There are some interesting examples of combinatorial libraries readily available on the internet.
A good example is at http://www.nature.com/nbt/journal/v26/n5/fig_tab/nbt1402_F1.html.
Techniques used in combinatorial chemistry
Combinatorial chemistry was first used in the 1980s as a technique for producing
large numbers of oligopeptides and oligonucleotides. Modern combinatorial
chemistry is now a critical step in the process of high-throughput screening,
which is necessary for the identification of lead compounds and lead optimisation
processes.
Solid support method
This was the first combinatorial technique to be used. In this method the starting
material is attached to beads of resin and divided into a number of portions. Each
of these is then exposed to a different reagent. The product, still attached to the
resin, can easily be separated from unreacted reagents and co-products and the
process can be continued for as many steps as necessary to produce the required
number of products.
In some cases the screening of the product can take place while still attached to
the resin.
Solution synthesis
If it is difficult to attach the starting material to a suitable resin, or if it is desired to
monitor the progress of the reaction while the product is being formed, then the
reactions can be carried out in solution, as in conventional synthesis. This does,
however, create problems in separating and purifying a large number of different
product molecules.
9.3: Drug discovery and design
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Unit 9: Medicinal Chemistry
Parallel synthesis
Both of these techniques are used in what is called parallel synthesis. A large
number of product molecules are synthesised at the same time and all of them are
screened concurrently. This is in contrast to more traditional methods of synthesis
where a single compound is made and screened, and the results of that screening
are then used to inform the decision about which molecule to synthesise next.
Portfolio activity (2.3, 3.1, 3.2, 3.3)
Write a description of the processes of drug discovery and design. You should illustrate your
description wherever possible with some examples of how these processes have been applied to
specific examples of drugs. Suitable examples could come from some of the drugs discussed in
Topic guide 9.4 – for example, the penicillins, ACE inhibitors such as captopril and anticancer drugs
such as methotrexate. In your description you should cover the following:
•• how drug targets are chosen and lead compounds identified
•• how structure activity relationships are applied to the design of the drug
•• how combinatorial chemistry is used in the in vitro or in silico screening of possible drug
candidates
•• how drugs are evaluated for biological activity and safety.
Checklist
At the end of this section, you should be familiar with the following ideas:
 large numbers of similar molecules need to be synthesised during the process of drug design
 combinatorial libraries are used to enable these molecules to be assembled.
Acknowledgements
The publisher would like to thank the following for their kind permission to reproduce their
photographs:
Shutterstock.com: isak55
All other images © Pearson Education
We are grateful to the following for permission to reproduce copyright material:
Dr Richard Lewis, Novartis International AG Investor Relations for a case study. Reproduced with
kind permission.
In some instances we have been unable to trace the owners of copyright material, and we would
appreciate any information that would enable us to do so.
9.3: Drug discovery and design
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