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George Karageorgis prepares reaction arrays

Mimicking natural evolution with ‘promiscuous reactions’ to improve the diversity of drugs

Taking their inspiration from evolution in nature, researchers in the Chemical Biology and Medicinal Chemistry group have developed a revolutionary new scientific method which will improve the diversity of ‘biologically active molecules’, such as antibiotics and anti-cancer agents. This research may uncover new pharmaceutical drugs that traditional methods would never have found.

The traditional method for discovering new drugs involves preparing new biologically active molecules by adjusting the chemical structure of an existing one slightly and analysing the results. This trial and error method is both time consuming and limits the variety of new types of drugs that are developed.

In nature organisms gradually evolve both the chemical structures and the methods to produce them over millennia because they are of benefit. Some amazing structures with really interesting biological activity are produced and this research tries to capture the essence of this approach to discovering new drugs.

There is a known problem with limited diversity in drug discovery. It’s like a baker always going to the same storage cupboard and using the same ingredients, yet hoping to create something that tastes different. This new novel approach however is like taking lots of different ingredients – including things you may never think will work together – and trying different combinations of these. If the result ‘tastes’ promising then it is used as the starting point for another set of experiments. Only at the end, when something really good as been identified, is it worked out what exactly has been made.

In the study the reactions of 12 types of diazo compound were investigated. Diazo compound reactions were chosen as they have many possible outcomes, depending on the specific reaction conditions (such as the temperature and concentrations used) and the choice of the reaction catalyst.

Different types and quantities of the reaction ‘ingredients’ were added to each of the 96 wells of an experiment tray and the products of the reaction were then tested to see if they had the required biological effect.

The key to this method is using very promiscuous reactions which can lead to many different interesting products. Normally, these are the sort of reactions that chemists would steer well clear of, but in this case it’s actually an advantage and provides the chance of finding some diverse and active structures.

To assess the effectiveness of the reaction products as drugs, the researchers studied how well they could activate a particular biologically relevant protein called the ‘androgen receptor’, which is important in the progression of certain cancers. The results informed two further rounds of experiments on the most promising candidates, from which the researchers eventually identified three biologically active molecules.

It’s very unlikely that anyone would have ever designed these molecules or thought to use these compound classes against this target, but using this methodology the results were reached very rapidly and efficiently. The beauty of this approach is that pharmaceutical companies could start using it tomorrow, as no specialist equipment is required.

The next step in this research is to run further studies and add even more diversity to the potential products of reactions to convince other scientists to adopt this new technique.

The research carried out by PhD student George Karageorgis, Dr Stuart Warriner and Professor Adam Nelson was published online in a paper, ‘Efficient Discovery of Bioactive Scaffolds by Activity-Directed Synthesis’, by the journal Nature Chemistry on 24 August 2014.