Summary of the material for the course pharmacochemistry. This includes pharmacokinetics, pharmacodynamics, pharmacology, drug discovery, molecular modeling (SBDD) and medicinal chemistry. It contains images aswell and this is a summary of all the course lectures
Introduction
Paracelsus: the dose makes the poison. There is a relation between dose and
effect. Morfine (afkomstig van een poppy -> opium -> morfine) hadden ze
geacetyleerd en hieruit ontstond heroine. Bij het acetyleren was de bedoeling om
een minder verslavende stof te creëren, maar heroine was nog verslavender.
Hieruit kwam dat een kleine verandering al een groot effect kan hebben. De
eerste synthetische drug was aspirine (acetylatie van salicylzuur). Softenon was
de eerste drug op de market in Duitsland en dit werd gebruikt voor morning
sickness during pregnancy. They did some testing on rats and they did not see
any side effects. Children born from the mothers that took these drugs had no
upper limbs. This was the start of the founding of the approval that companies
need to put the drug on the market. Het is belangrijk dat je probeert te begrijpen
hoe een bepaalde stof werkt op moleculair level. Je moet weten wat de target is
van het molecuul.
Pharmacological phase: study of the optimal dose of the drug
Pharmacokinetic phase: What the body does with the drug, the movement of the
drugs into the body
Pharmacodynamic phase: what does the drug do with the body, this gives the
effect so the change in the body caused by the drug.
1.2 Receptor pharmacology
Researchers try to optimize drug activity by looking at drug interactions with
receptors and quantifying these processes. The usefulness of a drug is
determined by the specificity and selectivity of the drug
- Specificity: the number of different type of receptors the drug can interact
with
- Selectivity: the property of a drug to exert a limited amount of effect. In an
ideal world the drug only has one therapeutic effect and no other side
effects.
Techniques to test as much of these molecules in a short time (high-
throughoutput). Using one of these three techniques you can see which one is
the best compound.
- Phenotypic screening: you administer all different type of compounds to
see if the phenotype changes of the model system (mouse, cells , etc) This
is without any hypothesis. You identify the best compound with the least or
no phenotypic effects
- Target-based screening: you select a certain target protein in the body that
you think is important to design a drug for to stimulate or inhibit the target
that is important for the disease. The effect on the target can be measured
, using a fluorescence compound to see if it has an interaction or not. In
vitro or in vivo screening assays are used to select the best compound
- Structure-based design: you need to know where the binding pocket is that
could bind the structure and you need to know the 3D structure for this. If
you know the pocket then you can design chemicals that fit into this
pocket (this technique is in development)
The discovery of first-in-class drugs is target-based or system-based.
Target based approaches are hypothesis-based approaches that aim to
manipulate a biological system by pharmacologically modulating a specific
component or target. For this you know the target.
- Small-molecule (NDA)
- Biologic (BLA)
System-based approaches are based on or monitors a phenotypic change in vitro
or in vivo
- Phenotypic screening: the testing of a large number of compounds, in most
cases randomly selected
- Chemocentric approach: in which compounds with known pharmacology
served as the starting point
Types of targets for drug action
- Receptors are proteins that are embedded in the plasma membrane of the
cell and they can bind hormones and neurotransmitters. Agonist or
antagonist can bind to the receptor to influence its function. Agonist are
compounds that can bind to a receptor and can result in an effect,
such as ion channel opening/closing, enzyme activation/inhibition, ion
channel modulation and DNA transcription. Antagonists are compounds
that binds to the binding pocket but it will not result in an effect
since it blocks the receptor from binding to an agonist. Here the
endogenous mediators are blocked.
, - Ion channels are proteins that are in the plasma membrane which are very
specific for a certain ion and they can be open or closed. The opening or
closing is very important is nervous tissue to transduce the potential. With
drugs you can influence that by blocking the pore so no ions can
flow through or that it modulates the open or closed state of the
channel
- Enzymes convert certain compounds into other that are beneficial for
metabolism. Inhibitors can block enzyme function and then the normal
reaction is inhibited. They can be used to convert the drug into a false
substrate that disturbs the cell and produces abnormal metabolites. Pro-
drugs are not active in the form that they are inhibited but by enzymatic
activity they are activated. This can be used for drugs that have difficulty
being absorbed so if you change the compound so it’s not active but can
be absorbed better you can activate them using enzymes.
- Transporters can be found overall in the body and they take up the
neurotransmitters and if you block the transporters you can increase the
amount of neurotransmitters in the brain or other types of the bodies.
Types of drug receptors
One way that you can distinguish these receptors from each other is to see how
the actual effect of the drug is taking place and how much time it takes
- Receptor-operated channels: here is a rapid signal transduction taking
place. When an ion passes, only hyperpolarization or depolarization takes
place before there is a cellular effect
- G protein-coupled receptors: it binds a ligand from the outside and the
binding leads to a cascade of intracellular proteins that start with G
proteins that are released and they can activate an ion channel or have
enzymatic function which leads to a formation of second messenger and
this can bring a lot of different reactions in the cell. This can lead to protein
phosphorylation, Ca2+ release or other cellular effects. This takes only
, seconds. Most drugs act on these receptors as they are involved with many
diseases.
- Enzyme receptors are both enzymes and receptors at the same time. This
is a protein that can bind a ligand from the outside but the protein also has
enzymatic function and by binding of the ligand it directly translates into a
change in the enzymatic function which can be increased or decreased.
This leads to protein phosphorylation which can influence gene
transcription or differences in protein synthesis. This takes hours
- DNA-coupled receptors: they act in the nucleus, in the DNA and these
molecules can freely diffuse across the plasma membrane in the cells and
these are recognized by binding proteins in the cytosol and this binding
does not directly lead to an effect but then the complex is transferred to
the DNA where it binds and this either promotes or inhibits gene
transcription. This has an effect or protein synthesis. This might take hours
or even days.
Drugome: 400 proteins that are produced by the diseaseome genes could be
targeted by drugs.
Technologies used in target discovery
- Genomics: when we look at the mutations in the genome and try to find
out what is happening in the disease. You look at the genetic modification
and post-transcriptional modification as well.
- Proteomics: here you research post-translational modifications
- Metabolomics: here you research if the metabolites have changed and
then you can know if there also changed something in the function of the
protein. Metabolites are produced by the enzymes and those are often
small molecules and these are easier to analyze using mass spectrometry.
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