Researchers find new way to create man-made molecules

Scientists in Leeds have devised a new way of creating man-made molecules in a breakthrough that could revolutionise drug development.

Creating new drugs to combat disease and illness requires the completion of a complex 3D jigsaw. The shape of the drug must be right to allow it to bind to a specific disease-related protein and to work effectively, and the core framework of the molecule determines this shape.

A team from the Astbury Centre for Structural Molecular Biology at the University of Leeds has developed a new approach, which allows the creation of molecules with an extraordinarily wide range of shapes.

Lead researcher Professor Adam Nelson of the University's School of Chemistry said: "Nature has created hundreds of thousands of molecules that have different frameworks and biological purposes, but in the global pursuit of new drugs, chemists from around the world are racing to create new molecules with functions not seen in nature."

The newly created molecules are being shared with colleagues in the Faculties of Biological Sciences and Medicine and Health to see if specific new molecular frameworks match the requirements of their own research.

"Making collections of similar molecules is great for optimising a biological property," said Professor Nelson. "But to put it simply, if researchers need a cube-shaped molecule to target a particular protein, they may well find that they can only choose from libraries stocked with millions of sphere-shaped ones."

Co-researcher Dr Stuart Warriner added: "Making molecules is a bit like making something using Lego bricks. Up until now we've only really become good at making the equivalent of a Lego car or train. There might be 30 million synthetic molecules registered, but there are probably several million of these that are the equivalent of Lego cars - they may have different wheels and wing mirrors, but their fundamental shape is essentially the same. We've not really scratched the surface of the possible structures that could be made. This lack of variety in the core shape of molecules may well limit the range of proteins that medicinal chemists can target."

The Leeds team has used "metathesis", a reaction that won the 2005 Nobel Prize in Chemistry.

Professor Nelson explained: We take simple building blocks, a bit like the amino acids that make up peptides, and we assemble them in different sequences using three simple reactions to link them together in a chain. The key difference is that we then add the catalyst, which initiates a "scaffold reprogramming reaction", which ripples down the chemical chain and restitches the molecule together in a completely different way each time."

The team has prepared molecules with 84 distinct molecular frameworks - and about two-thirds of the frameworks are unprecedented in the history of organic chemistry.