Picture 11. The Zaprinast molecule. Scientists knew this caused some vasodilation.
The search for Viagra™
When a new medicine is being developed, many thousands of compounds are tested before the best one is chosen for clinical trials.
The search for Viagra™
There was no exception in the development of Viagra™ but the researchers did have a starting point. They had already developed a medicine called Zaprinast that had some of the effects they were looking for. It had been developed as an anti-allergy treatment but had not been potent enough. However, it also caused vasodilation. Zaprinast inhibits the PDE enzyme and this was the effect that researchers were looking for in their search for a new anti-angina medicine.
They also had another clue. They knew that the vasodilation was caused by the actions of cGMP inside the walls of the arteries. The target for the new medicine was PDE that breaks down the cGMP (see page 3). The scientists had to design a molecule that had a similar structure to cGMP. This would indicate that it would block the active site of the PDE molecule and stop it breaking down the cGMP.
Picture 12. The cGMP molecule. This fits the active site of PDE which then breaks it down.
Matching structures
Look at the structure of cGMP and compare it with the structures of the molecules below. Which of the three new molecules would you choose to block the active site of PDE (remember, it should have a similar shape to cGMP to take its place in PDE's active site)?
Click on each molecule to find out what it is.
Caffeine This looks similar. It has a 5-sided ring joined to a 6-sided ring but does not have the additional ring that is found in the cGMP.
Caffeine is the active compound found in coffee. It acts as a mild stimulant. It also inhibits PDE but is very weak and not useful as a treatment.
Picture 13a.
Testosterone This compound contains 5-sided and 6-sided rings joined together but not in the same way as the cGMP.
Testosterone is involved in the development of male secondary sex characteristics and the production of sperm.
Picture 13b.
Viagra™ This is Viagra™. It has similar 5-sided and 6-sided rings (top right) and the extra rings attached (bottom left) to the cGMP and also Zaprinast.
Its shape is close enough to the cGMP so that it fits into the PDE enzyme's active site. This blocks out the cGMP and stops it from being broken down.
Picture 13c.
Picture 14. Viagra™ and Zaprinast as a comparison.
Virtual molecules
To aid in the design of molecules, computers are used to build virtual molecules. Designers can alter molecules in the computer which allows their three-dimensional shape and chemical properties to be predicted. This allowed researchers to design molecules that would be good candidates to test against the PDE. The technique allows compounds to be targetted more efficiently, but the development still requires many compounds to be screened in laboratory tests.
The shape of the Viagra™ molecule allows it to fit into the PDE's active site. This prevents the enzyme from breaking down the cGMP that causes vasodilation.
Lock and Key action of enzymes
Enzymes are very specialised molecules. Each one will work on only a very narrow range of molecules, called their substrate. That is because they work by what is called the lock and key method. The substrate fits closely into a part of enzyme called its active site. This is where the reaction takes place before the products are released.
It is called the lock and key method because only one substrate (the key) will fit into the active site (the lock). Picture 15 shows how this happens.
Picture 15. The enzyme PDE breaks down cGMP. Viagra™ inhibits the enzyme by blocking its active site.
The substrate fits into the active site like a key in a lock. Once it is there, the enzyme causes the substrate to react. The reactants are then released and the enzyme can work on another molecule of the substrate.
In this case, the enzyme is PDE and the substrate is cGMP. The PDE breaks down the cGMP.
Enzyme inhibitors
If a molecule (medicine) that closely resembles the substrate is introduced it can interfere with the reaction. These molecules are called competitive inhibitors. They will fit into the active site in place of the real substrate. The inhibitor prevents the substrate from fitting into the site.
By filling the active sites of a number of enzyme molecules, the reaction is slowed down. Adding more inhibitor slows the reaction more - because more sites are filled.
In this case, the inhibitor is Viagra™ and it stops the cGMP from being broken down by PDE.
