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Molecuul tot MedicijnH12 Drug discovery: finding a lead
Boeksamenvatting:
12.1 choosing a disease
Is there a need for a drug for the disease, what is the market, is there enough money and do they get
a good financial return for their investment.
12.2 Choosing a drug target
An understanding of which biomacromolecules are involved in a particular disease state is clearly
important. This allows identifying whether agonists or antagonists should be designed for a particular
receptor or whether inhibitors should be designed for a particular enzyme.
Sometimes it is not known for certain whether a particular target will be suitable or not.
Caspases = are a family of protease enzymes that catalyse the hydrolysis of important cellular
proteins, and which have been found to play a role in inflammation and cell death.
If a drug or a poison produces a biological effect, there must be a molecular target for that agent in
the body. The analgesic morphine, are natural products derived from plants and just happen to
interact with a molecular target in the human body. Targets with no lead compounds to interact with
them are orphan receptors.
Target specificity and selectivity is a crucial factor in modern medicinal chemistry research. The
more selective a drug is for its target, the less change there is that it will interact with different
targets and have undesirable side effects. In the field of antimicrobial agents, the best targets to
choose are those that are unique to the microbe and are not present in humans. Other cellular
features that are unique to micro-organisms could also be targeted. It is still possible to design drugs
against targets which are present both in humans and microbes, as long as the drugs show selectivity
against the microbial target.
Selectivity is also important for drugs acting on targets within the body. Enzyme inhibitors should
only inhibit the target enzyme and not some other enzyme. Receptor agonists/antagonists should,
ideally, interact with a specific kind of receptor (adrenergic receptor) rather than a variety of
different receptors. Receptor agonist and antagonists should also show selectivity for a particular
receptor subtype.
Targeting drugs against specific receptor subtypes often allows drugs to be targeted to specific
organs or to specific areas of the brain. This is because the various receptor subtypes are not
distributed uniformly around the body, but are often concentrated in particular tissues. In many
diseases there is a ‘transmission fault’ to a particular tissue or in a particular region of the brain.
Neurotransmitters are released close to their target receptors and, once they have passed on their
message, they are quickly deactivated and do not have the opportunity to ‘switch on’ more distant
receptors.
Pitfall: more than one target may need to be addressed for a particular ailment (kwaal).
,A single drug that can act selectively at different targets in a controlled manner – a multi-target-
directed ligand.
12.3 identifying a bioassay
Choosing the right bioassay or test system is crucial to the success of a drug research programme.
The test has to be done in vivo or in vitro. In vitro is with isolated cells, tissues, enzymes or receptors.
In vivo is with animals and often with transgenic animals, these are animals whose genetic code has
been altered. The affinity of drugs for receptors van be measured by radioligand studies.
Sometimes the validity of testing procedures is easy and clear-cut.
HTS is a process that is effective in identifying potential new lead compounds. The test should
produce an easily measurable effect which can be detected and measured automatically. HTS can
generate many false-positive hits, and there is a high failure rate between the number of hits, and
those compounds which are eventually identified as authentic lead compounds. One of the main
causes of false hits is what are known as promiscuous inhibitors . These are agents which appear to
inhibit a range of different target proteins and show very poor selectivity.
NMR =analytical tool to determine the molecular structure of compounds and to detect whether a
compound binds to a protein target. The time taken by different nuclei to give off this energy is called
the relaxation time , and this varies depending on the environment or position of each atom in the
molecule.
Affinity screening = A nice method of screening mixtures of compounds for active constituents is to
take advantage of the binding affinity of compounds for the target
Surface plasmon resonance (SPR) = an optical method of detecting when a ligand binds to its target
Scintillation proximity assay (SPA) = a visual method of detecting whether a ligand binds to a target.
It involves the immobilization of the target by linking it covalently to beads which are coated with a
scintillant
Isothermal titration calorimetry (ITC) = a technique that is used to determine the thermodynamic
properties of binding between a drug and its protein target— the binding affinity and enthalpy
change, in particular
Virtual screening = involves the use of computer programs to assess whether known compounds are
likely to be lead compounds for a particular target
Pharmaceutical companies tend to concentrate on developing drugs for diseases which are
prevalent in developed countries and aim to produce compounds with better properties than
existing drugs.
A molecular target is chosen which is believed to influence a particular disease when affected
by a drug. The greater the selectivity that can be achieved, the less chance of side effects.
A suitable bioassay must be devised which will demonstrate whether a drug has activity
against a particular target. Bioassays can be carried out in vitro or in vivo, and usually a
combination of tests is used.
, HTS involves the miniaturization and automation of in vitro tests such that a large number of
tests can be carried out in a short period of time.
Compounds can be tested for their affinity to a macromolecular target by NMR spectroscopy.
The relaxation times of ligands bound to a macromolecule are shorter than when they are
unbound.
SPR, SPA, and ITC are three visual methods of detecting whether ligands bind to
macromolecular targets.
Virtual screening can be used to identify compounds most likely to be active in experimental
screening
12.4 Finding a lead compound
Lead compound = a compound which shows the desired pharmacological activity.
The natural source has some form of biological activity, and the compound responsible for that
activity is known as the active principle. Most biologically active natural products are secondary
metabolites with quite complex structures and several chiral centres.
Th e study of medicines derived from natural sources is known as pharmacognosy, and includes both
crude extracts and purified active principles.
Plants have always been a rich source of lead compounds.
Microorganisms such as bacteria and fungi have also provided rich pickings for drugs and lead
compounds.
Also marine and animal sources are interested for lead compounds.
Venoms and toxins from animals, plants, snakes, spiders, scorpions, insects, and microorganisms are
extremely potent because they often have very specific interactions with a macromolecular target in
the body. As a result, they have proved important tools in studying receptors, ion channels, and
enzymes
‘me better’ drugs: offer improvements over the original drug.
The natural substrate for an enzyme can be used as the lead compound in the design of an enzyme
inhibitor.
12.5 isolation and purification
Th e ease with which the active principle can be isolated and purified depends very much on the
structure, stability, and quantity of the compound.
12.6 structure determination
structure determination is a relatively straightforward process and it is only when the natural product
is obtained in minute quantities that a full synthesis is required to establish its structure. Th e most
useful analytical techniques are X-ray crystallography and NMR spectroscopy
12.7 Herbal medicine
, Herbal medicines contain a large variety of different compounds—several of which may have
biological activity—so there is a significant risk of side effects and even toxicity.
A lead compound is a structure which shows a useful pharmacological activity and can act as
the starting point for drug design.
Natural products are a rich source of lead compounds. The agent responsible for the
biological activity of a natural extract is known as the active principle.
Lead compounds have been isolated from plants, trees, microorganisms, animals, venoms,
and toxins. A study of medical folklore indicates plants and herbs which may contain novel
lead compounds.
Lead compounds can be found by screening synthetic compounds obtained from
combinatorial syntheses and other sources.
Existing drugs can be used as lead compounds for the design of novel structures in the same
therapeutic area. Alternatively, the side effects of an existing drug can be enhanced to design
novel drugs in a different therapeutic area.
The natural ligand, substrate, product, or modulator for a particular target can act as a lead
compound.
The ability to crystallize a molecular target allows the use of X-ray crystallography and
molecular modelling to design lead compounds which will fi t the relevant binding site.
Serendipity has played a role in the discovery of new lead compounds.
A knowledge of an existing drug’s pharmacophore allows the computerized searching of
structural databases to identify possible new lead compounds which share that
pharmacophore. Docking experiments are also used to identify potential lead compounds.
NMR spectroscopy can be used to identify whether small molecules (epitopes) bind to
specific regions of a binding site. Epitopes can be optimized then linked together to give a
lead compound.
If a lead compound is present in a natural extract or a combinatorial synthetic mixture, it has
to be isolated and purified such that its structure can be determined. X-ray crystallography
and NMR spectroscopy are particularly important in structure determination.
Herbal medicines contain different active principles that may combine to produce a
beneficial effect. However, toxic side effects and adverse interactions may occur when taken
in combination with prescribed medicines.
College Finding a Lead
Drugs bind mainly to proteins
Interactions in nature are perfect
Drug targets:
A. Lipids: cell membrane lipids
B. Proteins: receptors, enzymes, carrier proteins, structural proteins tubulin
C. Nucleic acids: DNA, RNA
D. Carbohydrates: antigens and recognition molecules, cell surface carbohydrates
Target selectivity:
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