Leeds: Drug design based on molecular scaffolds

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Scientists at Leeds University have developed a new tool for drug design, based on the ability to develop novel molecular scaffolds.

The team from the Astbury Centre for Structural Molecular Biology say the technique approach allows the creation of molecules with an extraordinarily wide range of molecular frameworks, which are likely to have a wide range of biological functions.

Of the 30 million or so synthetic molecules made throughout the history of organic chemistry, many are based on an extremely small number of scaffolds, with the main differences being the groups attached at the periphery.

The technique makes use of metathesis, a chemical reaction in which scaffolds are linked together and then treated with a catalyst, which initiates a scaffold reprogramming reaction that ripples through the chain of scaffolds and restitches them together in a completely different way each time. The development of metathesis won the 2005 Nobel Prize in Chemistry.

The team from Leeds used the approach to prepare molecules with 84 distinct molecular scaffolds, without about two-thirds unprecedented in the history of organic chemistry. The work is a huge leap forward from research reported in 2003, which resulted in the creation of six scaffolds in a single process. It is also a significant improvement on more recent research in which around 30 scaffolds were created using a complex combination of different reactions.

The researchers deliberately chose to prepare molecules with structural features that are similar to those found in natural products. Work has begun to screen the molecules and the team are considering patenting molecules with novel biological functions.