How do you design a new drug?
We investigate the science of designing new drug molecules and how scientific advances are making it easier to develop better drugs.
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Researchers are working hard to understand the causes of Parkinson’s. It is through this understanding that we learn what is going wrong and come up with new treatments, with the hope that this will one day lead to a cure.
This concept of find and fix is fairly familiar to us — much of our world works this way. For instance, if your car breaks down, a mechanic will first identify the cause of the breakdown before attempting to fix the faulty part. But when it comes to fixing problems with our bodies, the process of identifying what is going wrong and then coming up with a fix is not as simple.
Unlike a car, which people have designed and built, there are many mysteries to how the human body works, particularly in the brain. Our bodies are also infinitely more complex than a car. While a car may have 30,000 parts, an average human cells is made up of in the region of 100,000,000,000 parts, called proteins. So finding the faulty part is somewhat more difficult.
Current treatments for Parkinson’s
Despite this complexity researchers have developed treatments for Parkinson’s. We know that the symptoms of Parkinson’s are due to the loss of dopamine producing cells in the brain. This small molecule is needed for the brain to communicate messages about movement. And the symptoms of Parkinson's arise when there is not enough dopamine.
Current treatments aim to replace the dopamine that the brain is not making, so that it can continue to communicate. But these drugs do not slow the progression of Parkinson’s. And while they work well for a time, ultimately the side effects of these medications become problematic.
The trouble is we don’t truly understand the cause of the cell loss. What we need to do is find out what is going wrong because, when we find the fault, then we can design a fix. And ultimately fixing the problems that are happening inside these dopamine producing cells will help us protect them.
Finding the fault
At the scientific discovery stage of the research pipeline, the problems in the cells are identified. We already know a number of processes in the cells are changed in Parkinson’s. The batteries of the cells, waste disposal and even protein production are all affected.
Proteins are at the heart of everything that happens in our cells. They are the workers of our cellular factories and there are over 21,000 different types of them. Many types of proteins are involved in the different processes that happen inside our cell, but a single faulty protein can have significant impact on how well the cell performs. And ultimately, if a cell is not able to carry out its normal functions well enough, it will die.
Another complexity is added when you consider that Parkinson’s may not be a single condition. The differences in individuals symptoms gives us the first clue that they might be different types of Parkinson’s, and we now know that different processes in the cells can be affected in different people.
But there is often common ground, there are a few processes that are more commonly affected. Researchers have already made headway into identifying the proteins at the heart of these — the proteins that new drugs should target to change the fate of the cell. And, if drugs can be developed to help these proteins work better, then it may be possible to slow or even stop Parkinson’s.
Developing new drugs
The first stage of drug development is to find molecules with the potential to interact with your protein of interest. You can read more about this in our previous blog post.
In the past, the traditional starting point was to test natural products for their ability to treat human conditions. There are many examples of where this strategy has produced drugs that are still in use today.
1. Fungi that helps your heart
Statins are a group of medicines that help to lower the risk of cardiovascular disease by reducing blood cholesterol levels. The first promising statin drugs were originally found in the 1970s. One in particular, called lovastatin, is still in use today.
The chemical in this drug was discovered as a natural product of a type of fungus, and tests showed that it could reduce the body’s production of cholesterol. Today the chemical in lovastatin is synthesised by chemistry specialists rather than being isolated from fungi.
2. Anti-cancer trees
A cancer drug called paclitaxel is another example where natural products have found a use for treating human conditions. After discovering its potential anti-cancer properties, from 1967 to 1993, almost all paclitaxel (trade name Taxol) came from bark of Pacific yew trees. But harvesting the bark kills the tree and the Pacific yew is relatively scarce.
Chemistry specialists struggled to make the complex molecule in the lab, but it was clear an alternative, sustainable source of supply of the natural product would be needed.
Fortunately chemists were able to find a semi-synthetic way to produce the molecule using the needles from another type of conifer, the English yew, which removed the need to kill trees to produce the drug. Nowadays the drug — which is still used to treat a number of cancers — can be made in the lab.
The era of man-made molecules
Today the most common method of finding potential drug molecules to develop is to use ‘drug screening’. This involves working through (or ‘screening’) a library of hundreds of thousands of random man-made molecules to find those that show promise. Pharmaceutical company AstraZeneca has over 2 million chemical molecules in their library!
As all proteins have slightly different shapes, the trick is to find a molecule that can interact with a protein because it has a complementary shape.
In this way, drug screening is similar to looking for a key that fits a lock. But instead of unlocking a door, these chemical keys can change the way that a protein works.
Finding potential drugs in this manner is like finding a needle in a haystack, and often only a handful of potential molecules are found in a drug library. But the companies that do this type of discovery have developed tools and techniques needed to automate and speed up the process.
A new way to develop drug molecules
Drug screening can help to discover molecules of interest but it relies on a promising molecule being part of your library. And, when it comes to developing this molecule, screening doesn’t give you much information about how the key and the lock fit together, or where this fit could be improved.
So researchers have developed a new way to identify promising drug molecules. Instead of testing pre-existing molecules, in the hope that a good fit already exists, they want to build molecules that specifically fit the protein locks. This technique they use is called fragment based design and involves using parts of molecules, or ‘fragments’ to design new drugs that fit the lock. If we use the key analogy, we can understand how this might work.
Building a key to fit the lock
First the researchers figure out what the protein looks like — small molecule fragments are used to explore the space inside the protein. And the fragments are used in different combinations to help pick the protein lock.
Special techniques are used to see how and where these fragments bind — giving the researchers a good idea of what the space inside the protein looks like. And from this they can develop a chemical key that fits perfectly.
There are advantages to this new method of finding potential molecules to work with. Fewer molecules need to be tested than in traditional drug screening approaches and scientists develop a good understanding of how molecules actually fit in the protein — a key insight for the next stages of drug discovery.
And this method of designing new drugs has already been fruitful for finding promising drugs to treat cancer and kidney disease.
Developing new treatments for Parkinson’s
We’re learning more about how to develop new and better drugs everyday, and the Virtual Biotech means Parkinson’s UK is in a position to make the most from these scientific advances.
Our virtual approach means we don’t need to build expensive laboratories and pay for all the latest equipment. We can stay agile — working with the companies and organisations that have the right skills and techniques to take our projects forward. This means we can benefit from the latest technologies, such as fragment based design, and help bring new and better treatments to people with Parkinson’s faster.
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