Abstract
Medicinal chemistry often requires compounds that adopt a very particular three-dimensional shape with well-defined conformational degrees of freedom. This allows for the exploration of pharmaceutical space and for precision complementary protein-substrate complexes to form and combat disease. Occasionally however, it is difficult to design compounds that are a suitable shape for a particular target site within proteins. In response to this difficulty, this research focusses on investigating the properties of shapeshifting molecules – namely bullvalene – a single compound that can rapidly interconvert between numerous subtly different structures in three-dimensional space. As way of analogy, consider a Rubik’s cube; where each constituent can move in any direction in three dimensions to rearrange colour. As such, a Rubik’s cube can adopt a vast number of colourful amalgamations. Imagine each colour is one of the 10 carbon-atom vertices of bullvalene; similarly each carbon atom can simultaneously rearrange with one another giving rise to molecular shape diversity within a single entity. Fluxional carbon cages of this type have been successfully1 exploited in developing chemical sensors for biologically active compounds. In addition, previous studies within our research group have shown that shapeshifting molecules can fluctuate between two distinct shapes in response to their surroundings in the transition from solution to the solid state2 and be used in the control of dynamic sp3-carbon stereochemistry3. Building upon this, we are currently investigating the shape diversity of bullvalene through in silico studies, including principle moment of inertia and exit vector analysis. We believe that the information gathered from these investigations will allow us to understand more complex problems in medicinal chemistry, for example in the field of bioisosteric scaffold design.
