The next generation of synthetic compounds and the development of new drugs

Leeds scientists have discovered a new way to make the next generation of synthetic compounds in a breakthrough that could revolutionize drug development

The preparation of new drugs to combat diseases and medical conditions requires the completion of a complex three-dimensional assembly. The structure of the drug must be precise so that it binds to a specific disease causing protein and works optimally, and this structure is determined by the isolated core framework.

Now, a research team from the Department of Structural Molecular Biology at the University of Leeds (Leeds) has developed a new approach that enables the creation of compounds with an exceptionally wide range of different frameworks, and consequently different and varied structures. It is likely that the new compounds will have a wide range of biological functions, meaning that they could be valuable starting points for the discovery of new drugs.

As the lead researcher, Professor Adam Nelson from the University's School of Chemistry, points out: "Nature has created hundreds of thousands of compounds with diverse structures and different biological purposes, but in the global hunt for new drugs, chemists from all over the world are competing with each other to create new compounds with original functions that do not exist in nature."

The chemists share the new compounds with their colleagues in the faculties of biological, medical and health sciences in order to examine whether a new specific molecular structure meets the requirements of their own research.

Among the approximately thirty million synthetic compounds prepared during the history of organic chemistry, many of them are based on a very limited number of specific structures, with the main differences being in the chemical groups located in their scope. "Preparing a collection of similar compounds is extremely important for optimizing biological activity," says the lead researcher, "but in simple terms - if researchers need a cube-shaped compound to bind to a specific protein, they may find themselves choosing only from compound libraries that only have a spherical shape."

One of the researchers added: "Making compounds is essentially similar to making a structure using existing Lego parts. To this day we have become great at making, say, buildings equivalent to a Lego car or train. Today there are about thirty million synthetic compounds registered, of which only a few million are the equivalent of Lego cars - they may have different wheels or side mirrors, but their main structure is essentially the same. We haven't really scratched the surface of the possible buildings that could be accepted. This lack of diversity in the skeletal structures of compounds may certainly limit the range of proteins that are a target for research by medicinal chemists."

The approach of the researchers from Leeds uses a metathesis reaction (Metathesis reaction, double conversion reaction) which awarded its inventor the Nobel Prize in Chemistry for 2005.

The lead researcher explains: "We take simple building blocks, similar to the amino acids that make up proteins, and then connect them in a different way using three simple reactions to bind them together in a chain. The key difference lies in the fact that at this stage we add a catalyst that catalyzes a "reprogrammed scaffolding reaction", which causes the original chains to unravel and reassemble them in a completely different way each time.

"The reaction is similar to a molecular pair dance in which the atoms in each molecule change partners - and the fascinating thing about it is that we can change the building blocks over and over again to get different combinations, so we have an efficient way to get a variety of final structures. The potential of this process is enormous," he says.

The team from Leeds used this approach to prepare compounds with eighty-four distinct molecular structures - and about two-thirds of these structures are unprecedented in the history of organic chemistry. The current study is a huge leap forward in relation to a previous study in 2003 which was a landmark in which six different structures were obtained in a single response. This study is also a significant improvement in relation to an earlier study in which about thirty different structures were created using a complex combination of separate reactions.

The team deliberately chose to prepare compounds with structural characteristics similar to those found in natural substances: "We already know that the replacement of a carbon atom with an oxygen atom is a common process that occurs in nature and has evolved for useful purposes," says the lead researcher.

"We do not intend to improve existing natural substances or drugs - rather, we want to create compounds with structures that nature has not yet created, or those that would have developed naturally only as a result of environmental stress conditions that would make them advantageous for the organism."

The work of scanning the new compounds has long since begun throughout the various departments of the university and promising initial findings have already been received. The team intends to patent those compounds with new chemical structures and improved biological activity.

The original news from the University of Leeds
http://www.leeds.ac.uk/media/press_releases/current/drug_future.htm