Blebbistatin is a small molecule used as a tool to study an important class of proteins known as the myosins. Nicholas Westwood, at the University of St Andrews, UK, and colleagues believe that tools more potent and specific than blebbistatin can be synthesised. In this hot paper, Westwood performs a combination of chemical and biological studies to identify which structural modifications can and cannot be accommodated in one of the aromatic rings of blebbistatin. Westwood describes more about his work in the short interview below. 

1. Please explain, for a non-specialist, the significance of your article. 

There are a myriad of ways that researchers can work together at the chemistry-biology interface. One area that is hot right now is the discovery and optimisation of novel chemical tools. These tools are used to help us understand the function of proteins in cells. In 2003, Professor Tim Mitchison FRS at Harvard Medical School identified a novel chemical tool for studying a class of proteins known as the myosins. This superfamily of proteins is involved in many of the force generating events that occur in man including muscle contraction. The tool that Mitchison discovered is called blebbistatin and is used extensively by the myosin research community. Like all chemical tools, however, it could be improved, in particular its potency could be enhanced and its selectivity tuned. The best way to achieve this is to modify its chemical structure and then assess the impact of the chemical change. Using a combination of biological techniques carried out in the laboratories of Professors Ivan Rayment (University of Wisconsin at Madison, USA) and James Sellers (National Institutes of Health, USA), we have started to explore the effect of making structural changes in one part of the blebbistatin core structure. This is the first in a series of reports where we have modified virtually every position available in blebbistatin. Protein-ligand co-crystal structures have enabled us to get an insight into the effect of the changes we made and the use of computational methods by Dr Ruth Brenk at Dundee has suggested some new ways forward. Along the way, we discovered some unexpected results in synthetic chemistry. This paper combines research from a large range of disciplines demonstrating what can be achieved by interdisciplinary research teams in academia. 

2. What has motivated you to conduct this work? 

I am driven by a desire to combine high level organic synthesis with challenging problems in biology. We do this through the discovery and optimisation of chemical tools. Whilst the ultimate application of these tools is in biology, through their use in helping us to unravel biological function, significant chemical input is required to deliver the best tool for the job. Blebbistatin is a fascinating compound. It has a very interesting tricyclic core structure and the synthesis of analogues is very challenging. Professor Rayment has a long standing interest and expertise in structural analysis of myosins by protein X-ray crystallography. By combining research interests and skill sets we have tried to move forward chemical tools based on blebbistatin ultimately looking to help researchers dissect myosin function more easily. 

3. Where do you see this work developing in the future? 

The real challenge in this area is identifying selective chemical tools for as many individual members of the myosin superfamily as possible. Maybe by tweaking the structure of blebbistatin this can be achieved, maybe it will take the discovery of brand new pharmacophores to achieve this. Either way we believe the science is interesting, challenging and worthwhile. 

4. Are there any particular challenges facing future research in this area? 

In the paper we comment on the fact that it is relatively surprising that blebbistatin itself exhibits any real selectivity within the myosin superfamily given how similar myosin isoforms are in the general region of the protein where blebbistatin binds. The challenge of tuning selectivity is pretty enormous in any system and the myosins are no different. Our approach to this has been to put together synthetic routes to access lots of blebbistatin analogues and then to pick selective analogues from the overall collection. More recently we have also brought on board Dr Ruth Brenk from Dundee whose expertise in molecular modelling may also help us to prepare selective analogues in the long run. It has been great fun working in this collaboration and we have managed to overcome successfully the challenges of being located all around the world.