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Extensive Summary of Pharmacochemistry
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This is an extensive summary of the course Pharmacochemistry. This summary contains images as well.
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PharmacochemistryLecture 1.1 & 1.2
Already 2000 BC the beneficial effects of a plant described in the Greek codex → the poppy plant,
help to relieve fever and pain. They know the beneficial effects, but they did not know the
compounds of the plant that helped for this effect.
In the middle Ages they treated syphilis with mercury. So in this point in time chemistry was still in
his infancy. But the people cut purify compounds like mercury. Mercury has an antibacterial effect.
Paracelsus (1493-1541) → had an important statement how to treat patient with compounds from
plants or chemicals. He can be considered as the founding father of pharmacochemistry and
toxicology. The important statement was that he said ‘The dose makes the poison’. So dependent on
the dose the compound has a beneficial effect or it can turn out into a poison.
Digitalis purpurea (foxglove, vingerhoedskruid) → in the 18th century William Withering found that
extracting digitalis purpurea and make a tea of it and then give it to patients who are suffering from
oedema (fluid retained in the body, swollen ankles). William found that the patients then started to
produce more urine and loose the oedema fluid and then get a better condition.
First synthetic pharmaceutical drug → so this was prepared by chemical synthesis. It was based on
salicylic acid, which is a compound which is part of the bark of the silver willow. It was know that
extraction of the bark of the silver willow will help to cure fever, flu and pain relieving activity.
Salicylic acid was extracted as the active compound, this was used as a drug and it was indeed curing
fever and pain killer. But it had some side effects in the stomach (bleeding in the stomach).
- Felix Hoffman → trying to change the structure of salicylic acid, and then that it keep the
beneficial effects (flu and pain) and that it has no side effects anymore. So he boiled salicylic
acid in acetic anhydride and then the compound he got was acetylsalicylic acid (Aspirin) and
acetic acid. And indeed aspirin was a good pain killer and cured flu and fever and it has really
low side effects on the stomach.
Another compound that was isolated via chemist from the poppy plant → this was morphine, people
treated patients with morphine when they had severe pain. Morphine was stronger than aspirin, but
it is also addictive. They did the same as for producing aspirin, namely acetylate morphine. Di-acetyl
morphine was the compound that was received, this was then known to cure cough. But the problem
was that it was even more addictive than morphine (the name for di-acetyl morphine was heroin).
Thalidomide tragedy (1957) → then people knew that they had to test drugs before marketing it.
Softenon was sold as a drug that was treat to cure nausea and sleeping disorders, particularly for
pregnant women. It was soon recognized that the children that were born from mothers who took
softenon, had no upper limbs.
Molecular action of digitalis and subsequent events → dioxin is the main component of foxglove.
Dioxin is better to give via injection iso tablets. The patients who receive dioxin have a weak heart, so
not pumping enough and therefore there is fluid from the circuit going to the tissues leading to
swollen ankles. Dioxin interacts with the heart and not with the kidneys.
Pharmacological phases:
1. Pharmaceutical phase = disintegration and dissolution of the active compound
, 2. Pharmacokinetic phase = absorption, distribution, biotransformation, excretion → so really
what happens with the drugs inside the body
3. Pharmacodynamic phase = drug-receptor interaction
Stages in the drug discovery process:
In Europe the FDA is called the EMA. The drug is sometimes really expensive, since the
pharmaceutical company tries to get the money back they spend during the whole process of
developing the drug, which takes about 12 years.
High-content high-throughput drug discovery:
- Phenotypic screening → you have a large library of chemical compounds and then test them
in different types of models (cells, animals, drosophila, mice) with a typical disease
phenotype or healthy. Then test phenotypic screening assays and then the best compound
will be identified
- Target-based screening → select a certain protein/receptor that is involved in a disease and
you want to target in the disease and then test it with the large library of chemical
compounds. Then test if some compounds will bind or modulate with the target of interest
and that it will give a positive effect. So then the best compound will be identified
- Structure-base design → design and optimization of a chemical structure with the goal of
identifying a compound suitable for clinical testing. It relies on having knowledge of the three
dimensional structure of the molecular target for drug, the principle means of deriving the
3D structure are X-ray crystallography and solution NMR, alternatively it may be possible to
build a homology model based on a related protein.
Discovery of first-in-class drugs → these drugs have a new mechanism of action. You can also have
drugs with a different structure but with the same mechanism of action, so these are copies of the
first-in-class drugs.
You can have target-based or systems based drugs that are first-in-class drugs.
- Target based → then you know which target you want to aim for (receptor/protein).
o Target based approaches → Hypothesis-based approached that aim to manipulate a
biological system by pharmacologically modulating a specific component or target
(enzyme, receptor)
o Small-molecule (NDA). Screening, chemocentric/rational design
o Biological (BLA)
- Systems-based → is more hypothesis drive, you check for certain compounds or changes in
the system and then hopefully find a new target
, o Chemocentric approaches → in which compounds with known pharmacological
action (plants) served as the starting point and then you try to optimize this and
strengthen the potential of the compound, using this to design new molecules
o Phenotypic screening → the testing of a large number of, in most cases randomly
selected, compounds in a systems-based assay.
o Systems-based approaches → hypothesis-agnostic assay or approach that monitors
or is based on a phenotypic change in vitro or in vivo. Here you screen a lot of
compounds and do a lot of testing and then hopefully you find new
compounds/molecules that gives you new first-in-class drugs.
Types of target for drug action:
There are different types of drug receptors: it differs by the way they act, but also the rate at they
transfer a signal from outside to inside differs.
Marketed small-molecule drug targets:
- Enzymes
- GPCRs
- Ion channels
- Transporters
, - Nuclear hormone receptors
- DNA
- Integrins
The genome consist out of about 25000 genes. About 1800 of this genes are known to cause a
disease, this is called the diseaseome. These genes can be potential genes to target for drugs.
Nowadays about 400 different proteins are targeted by about 1200 different first-in-class drugs, this
is called the drugome. There are more drugs, but many of the drugs act on the same mechanism.
Every gene has about 4 splice variants and every protein that is produced has about 4 post-
translational states. So this means that there are about 400000 functionally distinct proteins.
Technologies used in target discovery → You can compare genes from healthy with disease people
and check if there is something wrong at the gene level. You can also compare proteins (so
proteomics) from healthy and disease people, but this is very difficult. Furthermore you can do
metabolomics, so compare the metabolites. What you can do by then is compare with mass spec
chromatograms, then the peaks can be different and this can give a clue which metabolite is
different. Then you can go back to which proteins might be involved in these metabolites. Then you
can design drugs for the protein.
In the oncology the most drugs are approved and developed. Small molecule drugs are mostly being
approved (73%).
Pharmacochemistry are drugs up to <10000 Da of molecular mass (aspirin/insulin). After that the
drugs are from pharmaceutical biology (HGH, EPO, mAbs).
Many reasons for drugs failure in clinical trials, here the drugs are developed from the lab table,
passed the animal studies and the Phase I. Mostly the efficacy fails in real patients (52%), here better
animal models/studies are needed. Then for 24% the safety fails, or the toxicity.
Drug-receptor interaction:
Drug binds to a receptor with an association, this binding [DR] is reversible.
This can be measured; take tissue you are interested in (from the heart) and
look at the receptors in this tissue. Then incubate the tissue with the drug of choice (usually this is
radio-labelled, because then easy to measure). Then there will be an equilibrium, then the fluid with
tissue and receptors will be measured for radioactivity, and then you can see how many drugs were
bounded to the receptors.
Determination of specific binding:
You have the total binding, that is the
binding of all the radioligand to the
receptors but also to the membranes in
between. This is something you do not want,
you want the specific binding, so just binding
to the receptors. What you do is then first give a protecting ligand (not
radioactive) then all the receptors will be occupied with this ligand.
Then you give the radioactive ligand and these ligands will only bind to
the non-specific binding sites (in between the receptors). After that
you can couple these two curves of total binding and non-specific
binding, to get the specific binding curve.
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