Samenvatting Medicinal Chemistry (van Molecuul tot Medicijn) / Farmaceutische wetenschappen

Samenvatting van het boek van Medicinal Chemistry (deel2) voor het vak van Molecuul tot Medicijn op de VU.

Preview samenvatting (4 van de 18 pagina's)

Summary Medicinal Chemistry Part 2
Van Molecuul tot Medicijn
Sjors van Heuveln
2‐SBI
13‐03‐2013

H12 Drug Discovery: Finding a Lead ........................................................................... 2
H16 Combinatorial and Parallel Synthesis ............................................................... 6
H18 QSAR (Quantitative Structure‐Activity Relationships) ................................ 8
H17 Computers in Medicinal Chemistry ................................................................. 13
H13 Drug Design: Optimizing Target Interactions .............................................. 16
Literature .......................................................................................................................... 18
© 2013 Sjors van Heuveln
H12 Drug Discovery: Finding a Lead
Drug Design and Development Stages
This process is subdivided in the next stages.
Choosing a Disease
This is mostly an economic choice for strategists. Revenues on the medicines need to
outweigh the costs. Therefore a lot of medicines are oriented on western diseases.
After choice of disease a target needs to be chosen.
Choosing a drug target
Targets are:
‐ Lipids: Cell membrane lipids
‐ Proteins: Receptors, Enzymes, Carrier proteins, structural proteins
‐ Nucleic Acids: RNA, DNA
‐ Carbohydrates: Cell surface carbohydrates or antigens and other recognition
molecules

It is important to know everything there is to know which biomacromolecules are
involved in the disease.

Discovering drugs was first about finding a drug, for example in plants. Nowadays,
due to discovery of proteins, chemists are designing drugs. Advances in genomics
and proteomics are revealing more and more targets and increase our
understanding of the biochemical workings of the human body. Orphan receptors
are possible targets, but their endogenous ligands are unknown. Combinatorial
synthesis helps in designing ligands that fit these receptors.

Drugs can be designed on differences between species and thus can be selective and
specific. For example antibiotics van function on due to anatomical differences
between prokaryotes and eukaryotes. Even when they have the same functional
proteins, drugs can still be selective, as minor differences exist in the amino acid
sequences of the proteins to be targeted.

Even between different subtypes of receptors or isozymes, drugs can be made
selective. This allows tissue specific action, as these subtypes are not equally
distributed around the body. Especially for neurotransmitter drugs, this is important
as these medicines will travel through all bloodstreams and can thus be very side
effect prone.

Not all medicines have a single target to be effective; some diseases need more
targets to be addressed. For example asthma needs a bronchodilator and an anti‐
inflammatory. Also some drugs become less effective over time, as functions may be
taken over by other proteins.

Multi‐target drugs are designed to target a range of different targets; these are
promiscuous ligands or dirty drugs.
© 2013 Sjors van Heuveln
Choice of Bioassay
In vitro tests
Tests not on live animals, but on tissue, cells, molecules, bacteria, etc.. They are
suitable for High Throughput Screening (HTS). However they only gain information
on pharmacodynamics, very rarely on kinetics.
In vivo tests are more used nowadays due to genetic engineering. This has made it
possible for bacteria to produce certain proteins/enzymes that are needed for
testing. Radioligand studies are then being used to measure the affinity of drugs on
targets.
In vitro test are usually carried out first, as it is important that it’s clear that the drug
will bind to the target.

In vivo tests
In vivo tests are tests on animals and humans. They gain information on
pharmacodynamics and pharmacokinetics and also information on side effects and
toxicity (LD50 en ED50)
Transgenic animals have human genes incorporated that code for the drug target.
In vivo test might also not be accurate, as they may prove potent in animals but not
in humans or even the other way around and thus will never be tested on humans.

Screenings
HTS, is failure prone because:
High false‐positive rate e.g. promiscuous inhibitors. These actually don’t bind, but
form aggregates that disable the target. However this doesn’t work in vivo as drugs
will spread throughout the body. Also chemical reactive agents can irreversibly bind
to targets. This is unwanted as HTS searches for reversible inhibitors.
However HTS can screen a lot of compounds in a short time.

Nuclear Magnetic Resonance (NMR): Measures relaxation time of atoms resulting in
a NMR‐spectrum. Relaxation time changes when molecules are bound. The greater
the molecule the shorter the relaxation time will be.
NMR can help detect promiscuous inhibitors in HTS.

Surface Plasmon Resonance
Is an optical method to detect when a ligand binds to its target. Gold layer and
polarized light.

Scintillation Proximity Assay (SPA)
Functions through targets that are covalently bound to beads. The known ligand is in
solution with the target and has I125 labelled to it. I125 is an energy donor and the
scillant‐coated bead is an energy acceptor. When binding takes places, there will be
emission of a photon, which can be detected. If now a potent compound is
introduced in the solution, less light will be emitted when also this compound is able
to bind to target.

Isothermal Titration Calorimetry (ICT)
Measuring thermodynamic properties of binding between drug and target.
© 2013 Sjors van Heuveln

Virtual Screening
Pre‐selection of compounds through virtual docking and prediction of compounds
that might be active in experimental screening.
Finding a Lead Compound
Is the next stage after the target is chosen. They may come from the natural world,
synthetic world or the virtual world.

Screening of natural products
Can be a rich source of finding lead. However these products are often difficult to
synthesize. Sources are:
‐ Plants (taxol)
‐ Microorganisms (penicillin)
‐ Marine life (rich in antitumour agents
‐ Animals (frogs)
‐ Venoms and toxins (are highly potent as they are already selective)

Medical Folklore
Many compounds were found through ancient medicinal practices.

Screening Synthetic compound libraries
Many pharmaceutical companies have big databases of compounds that never made
it to market. However they are often variations of the same base‐molecule. Often
compounds are bought from universities, who can have a lot of experimental
material.

Existing Drugs
Using patented compounds and modify it in such a way that it doesn’t infringe the
patent. They can offer improvements and thus a competitive advantage in the
market.

Starting from natural Ligand or Modulator
Natural ligands are a good first start in searching for the lead compound. They can
be used either for agonists or antagonists. Antagonists are being achieved by adding
extra binding groups. For orphan receptors this start is difficult as the natural ligand
is unknown.
Also enzyme products can be used in finding leads for enzyme targets.
Finally also modulators can be used as lead compounds as many proteins are under
allosteric control from a secondary binding site.

Computer‐aided Design of New Compounds
Through X‐ray crystallography the structure of the binding site can be determined.
Molecular modeling can then be used to further study the binding site.

Serendipity
Finding new drugs by accident and often not purposefully sought.
© 2013 Sjors van Heuveln