How it Works: Fragment Screening

     

 
 
Fragment screening is one of the newest and most exciting techniques out there. Why, exactly – you ask? Well, it offers scientists who design new medicines something really special: a glimpse into the future.
 
With fragment screening, scientists can get away with testing only a few hundred tiny chemicals, what they call ‘fragment compounds’, to see if any of them might be the foundation for what could eventually become a new drug.
 
In the past, nobody thought there was useful information to be had from fragments that small – that only much bigger compounds, which are expensive and tricky to work with, could demonstrate potential to become a drug.
 
But we now have the technology to discern vital insights from tiny compounds – just a dozen or so atoms big. This means we know, right at the very start, whether they are worth pursuing or not.
 
Fragment research is a recent and burgeoning field: one with the power to help produce drugs quicker, cheaper and smarter than ever before. And it’s a big deal, because if we can anticipate the potetial of our compound right at the beginning, then time is on our side.
 
 
What is it?
Screening compounds for future drug potential is nothing new.
 
Drugs generally work because the chemical make-up of the medicine reacts in a precise way with proteins in the body. Proteins are the machines of life, and drugs act by binding to very specific proteins – the “targets” – in ways that suppress biological processes which support disease – like those that lead to headaches or hayfever.
 
And so, for years, scientists have been developing increasingly sophisticated techniques that allow them to study the interaction between their protein target and different chemical combinations in search of the perfect drug.
 
But it’s not always simple: in the past, we could only detect a potential drug by looking at big, complicated compounds – we just couldn’t properly study the smaller ones.
 
Bigger compounds mean more complexity, and more complexity means less chance of getting a successful interaction between the compound and the target. So we had to sift through many big compounds to find the future drug – a very expensive process. What’s more, regular screening can offer up a lot of red herrings: compounds that look promising but, after much time and expense, turn out not to work after all.
 
But fragment screening offers something different. The technique allows scientists to identify whether tiny fragments of compounds are actually connecting with the target protein. The simplicity of the fragments makes it more likely we’ll get a hit: a weak hit, but a hit nonetheless.
 
And because we can screen many more of these fragments, compared to the bigger, trickier compounds, we stand more chance of getting a hit – like having lots of tickets for a lottery.  
 
But any success is then followed by the hard work of improving the potency of the compound by making small tweaks to its chemical composition, which eventually results in a lead that could generate a functional drug. Fragment screening means that we need to test far fewer compounds to find that potential drug. Scientists can identify suitable candidates early on without the hassle and heartbreak of many failed attempts. 
 
 
 
 Screening fragments may eventually result in a lead for a potential drug
 
The History

Fragment screening is still a relatively young technique. It was first proposed back in the 1980s, but it wasn’t until the turn of the 21st century that scientists really learned how to understand its subtleties.
 
A decade later, in 2011, the first fragment-based drug hit the market – Vemurafenib: an oral treatment for late-stage melanoma, followed in 2015 by Venetoclax: a treatment for chronic lymphocytic leukaemia.
 
Dozens of other fragment-based drugs are currently in clinical trials, and we can expect many more of these treatments to become available in the coming years.
 
Fragment screening is still at the beginning of its story, but if recent results are anything to go by, we could be at the start of something pretty exciting for drug design.
 
 
Fragment Screening at Diamond

Diamond’s very own fragment screening facility, known as XChem, attracts scientists from around the UK because it uses the most sensitive techniques available to detect binding between fragments and proteins.
 
XChem  allows scientists to test a thousand compounds during a single visit, and its sensitivity makes it easier than ever for scientists to seek out promising drug candidates.
 
The facility was developed in partnership with the University of Oxford, and is free to use if the results are to be shared publicly. Scientists come from all over the UK and further afield to use the cutting-edge tools.
 
And with each fragment tested at XChem, we move closer to better drugs and better results for patients. All of this without the need for extensive preliminary testing before we know whether a compound has a chance.
 
Ultimately, fragment screening saves us many hours, months and years of wasted time pursuing dead ends. And when it comes to creating new drugs: time is the most precious commodity of all.
 

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