There are many different ways of delivering medications to the body in a specific, purposeful way.
So far, around 500 molecular structures have been identified that act as targets for drugs.
Most of them are receptors and enzymes, but they also include ion channels, nucleic acids, transport proteins and ribosomes.
Nowadays specialists from various scientific disciplines work together in developing new medications
–a field known as ‘drug design.’
This kind of directed research on medications has mainly gathered pace since the 1950s.
In the early days of pharmacology in the late 19th century new medications were generally discovered by chance.
Many drugs that are still in use today were widely used
long before their mode of action and their precise targets in the human body were known.
A good example is ASPIRIN.
Its active agent, salicylic acid, was already indirectly known to the Egyptians 3,000 years ago
as a treatment for fever, pain and inflammation.
Aspirin was first synthesized in 1897, but it was not until 70 years later
that its mechanism of action was discovered by John Vane.
Aspirin inhibits an enzyme called cyclo-oxygenase, thus preventing the body from making transmitter substances
that increase the sensitivity of pain receptors.
Together with Sune Bergström and Bengt Samuelsson, Vane was awarded the 1982 Nobel Prize for Physiology or Medicine.
The 20th century saw many significant innovations in drug design, for example PRONTOSIL.
This red dye, which belongs to the class of sulfonamides, was the first commercially available synthetic antibiotic.
Sulfonamides inhibit the synthesis of folic acid in bacteria, thus preventing them from making DNA and reproducing.
The discovery of Prontosil kicked off the “Age of Antiobiotics”
that soon blossomed with the development of penicillin and streptomycin.
In 1939 Gerhard Domagk won the Nobel Prize in Physiology or Medicine for his research on the antibacterial action of Prontosil.
But how to tackle viral infections?
In this area great success has been achieved with so-called anti-metabolites such as ACICLOVIR.
This substance is mistaken for a nucleoside base by the virus which then incorporates the drug in its DNA synthesis.
That causes chain termination, so the virus can no longer replicate.
Gertrude Elion and George Hitchings carried out pioneering work in this area.
Elion also developed a number of cytostatic drugs to treat cancers.
And she was involved in the development of AZIDOTHYMIDINE (known as AZT), another modified nucleoside analogue.
This substance prevents viral replication by competitively inhibiting the enzyme reverse-transcriptase.
In 1987 AZT became the first U.S. government approved medication to treat HIV/AIDS infection.
What I simply want to share with you is a feeling of optimism that we know have
that we can do something more for AIDS-patients than we have been able to do in the past
by understanding something about the mechanism by which these drugs work
but also understanding that the only way we are going to get away from resistance is going to be with combination-chemotherapy.
Elion and Hitchings shared the 1988 Nobel Prize for Physiology or Medicine
with Sir James Black for their important discoveries in drug development.
But of course people also reach into the medicine cabinet for less serious conditions than HIV/AIDS.
Nowadays for example, high cholesterol levels can be treated with pills: like ATORVASTATIN,
a member of the drug class called statins.
It works by blocking hydromethylglutaryl-CoA-reductase, an enzyme that is responsible for cholesterol production in the body.
Statins are the world’s best-selling medications.
In 1964 Konrad Bloch and Feodor Lynen received the Nobel Prize in Physiology or Medicine
for elucidating the complex mechanism of cholesterol synthesis.
Another Nobel Prize went to Michael Stuart Brown and Joseph Goldstein
‘for their discoveries concerning the regulation of cholesterol metabolism’.
Around a third of pharmaceuticals available today act on G protein-coupled receptors.
Examples are antihistamines, antidepressants, and blood pressure lowering medications.
G protein-coupled receptors, GPCRs for short, are a superfamily of receptors located in the cell membrane
that transmit visual, hormonal, neuronal or other signals and play an important part in cell communication.
The receptors’ mode of action involves bonding of specific ligands –and this is the point that many medications target.
The use of GPCRs in the pharmaceutical field goes hand in hand with progress in protein biochemistry.
Modern methods have led to a better understanding of membrane proteins and their interactions with other substances.
The use of GPCR models is an example of targeted structure-based drug design.
In 2012 Robert Lefkowitz and Brian Kobilka were awarded the Chemistry Nobel Prize for their work with G protein-coupled receptors.
So what insights can we get from structural biology?
Well first of all it's necessary to be able to get protein structural information.
And to really understand the process we want to get inactive states, shown in red.
We want to get active states, shown in green.
And we'd like to get this intermediate state which is agonist-bound but not coupled.
And this turns out to be the most challenging, as shown by the wiggly box, because it's very dynamic.
And I’ll go into that in a few minutes.
So how do we get structures?
Well there are several ways of getting structures.
It's possible to get structures by NMR and electron microscopy
but the current state of the art is that for proteins the size of GPCRs the best method is crystallography.
So as you’ve heard one tries to prepare protein so that it’s highly uniform,
you can form crystals and crystals are then placed in an X-ray beam.
The diffraction pattern can be used to calculate the structure of the protein.
Pharmaceutical research has undergone a transformation since its beginnings.
In today’s drug design little is left to chance and targeted approaches are constantly being improved.
Hypothetical target structures can be screened rapidly with fully automated high-throughput methods
to test for their interactions with thousands or even millions of substances.
But this doesn’t necessarily mean that more drugs are being developed.
The effort involved in bringing a new medication onto the market is still immense.
The trend is moving away from the traditional ‘one target – one disease – one drug’ dogma to a more holistic approach
that includes personalized treatment methods to improve our ability to deal with disease.