Profile

I’m a medicinal chemist – which means I try to find the next drug to treat disease. The drug discovery process is long, complicated and costly. It can take decades and cost billions to develop a new treatment, and it is never a one-person effort. I work as part of a team with other scientists, including biologists, pharmacologists, analytical and computational chemists. Later on in the process, engineers, doctors and the dreaded lawyers get involved!

Whilst we call the process of finding a new drug “drug discovery” it is more like engineering than a treasure hunt. First, we need to understand what is going wrong in our bodies that results in us getting ill. If you imagine the London Underground – it is a complex network of trains, signals and stations – and most of the time it works well. But when it breaks, there is chaos until the cause is understood and repaired.

Each cell in your body is similar – only the network is much more complicated and, (since we didn’t build it ourselves) when it goes wrong we often don’t know why. Biologists spend years trying to tease apart and understand the network, so they can trace the fault that is causing the disease. This “fault” is often an protein (an enzyme or receptor) or sometimes a piece of DNA or RNA that has gone wrong. We call this a “target” – and if we “hit” our “target” we cure the disease.

It is the job of chemists like me to find a molecule that hits our target. We do this by screening vast libraries of up to a million known compounds that we keep in stock to identify starting points. Below is a picture of one our robots “plating”  compounds in solution for testing.

We then refine these molecules, adding and subtracting functional groups (such as amines, acids, esters, alcohols) to improve our compound. It’s a bit like playing with Lego (only we don’t have picture to go on). Of course, there are a lot of parameters that need to be refined to make a drug. For example, there is no point being able to hit your target really well if your compound won’t dissolve in water or is toxic. We therefore work with biologists and pharmacologists to test our compounds for many parameters. Once we’ve found a compound with the right balance of properties we move forward to animal testing.

Animal testing is, of course, controversial. Whilst we do our very best to minimise the use of animals, the sad reality is that we can only prove our molecules might work and are reasonably safe for people by performing animal tests. Indeed, there are some diseases – for example HIV, Alzheimer’s and most mental illness – that can never be properly reproduced “in a test tube”. Tragedies like thalidomide would not have happened if today’s standard of animal testing had been performed, and chemists remember this painful lesson very well. We were and are responsible for every “thalidomide baby” and we cannot allow that to happen again. Animal testing is one of the most tightly regulated aspects of our work, second only to human trails themselves in terms of the amount of oversight and documentation we have to provide to show they are critical for project progression.

If our molecule is safe and works in animals, we then move to human testing. This takes up to 10 years to complete and is by far the most expensive part of the process. It is also the point where we often fail! In fact, drug discovery has a 95% failure rate and most medicinal chemists will go their entire careers without every getting a new drug into patients on a global scale. The reasons for failure are the subject of much debate amongst my industry – it comes back to our incomplete understanding of how our bodies really work.

Despite these challenges, I love my job because I feel I am making an effort to help people in a way most people can’t imagine. Even the best surgeon or doctor in the world will only save a few hundred or thousand lives in their careers – I have the potential to save millions in mine!!

Okay a little joke there!

Because medicinal chemistry is a cycle of making, testing and improving your molecules until they reach certain standards, it is often difficult to explain how we do it.

The making of molecules involves synthetic organic chemistry. I use the knowledge from my education and work experience, as well as online databases, to find ways of making the molecules I want to make. I make these in the lab, usually performing 20-30 reactions at the same time. You can see some of the equipment we use to performed multiple reactions in parallel below.

The difficult part is not putting on the reactions, but rather isolating your desired compounds from the mixture. This process, called purification, is the true art of organic chemistry and there are many techniques available. I am lucky in my work that we have robotic equipment that can purify compounds automatically, so I can spend more of my time designing the next round of compounds to make. Here is a picture of one of our pieces of automated purification equipment – a large scale HPLC-MS (high pressure liquid chromatography-mass spectrometer) machine

The “design” process is the hardest to explain. Essentially it’s a bit like playing with Lego – we add or remove bits the nolecule and trest to see what effect this has on the properties (activity, toxicity, solubility etc.). We bring together information from many similar molecules (called analogues) into a “structure-activity relationship” (SAR). We study the SAR for trends that help us to understand what to do next with our Lego! We can add to our understanding by using computational models or real pictures (generated by X-ray) or our molecules hitting our target.

When we make a compound, we need to confirm its identity and purity before we can test it. Tests in cells use compounds of >95% purity, whereas tests in animals require compounds >98% pure. We use nuclear magnetic resonance (NMR) and mass spectrometry (MS) data to confirm the identity and purity of our compounds – here’s a picture of our NMR machine and an example of the data it gives us.

I spend about 50% of my time in the lab, 25% of time on computers researching ideas and analysing data and about 25% of my time managing my team of about 6 people – which mainly involves writing reports and presentations for my bosses!