Using ‘smart materials’ to develop new drugs
Researchers at Imperial College London and the University of Surrey have developed a more effective method for making proteins crystallize, using “smart materials” that remember the shape and characteristics of the molecule.
The process of developing a new drug normally works by identifying a protein that is involved in the disease, then designing a molecule that will interact with the protein to stimulate or block its function. In order to do this, scientists need to know the structure of the protein that they are targeting.
A technique called X-ray crystallography can be used to analyze the arrangement of atoms within a crystal of protein, but getting a protein to come out of solution and form a crystal is a major obstacle. The number of proteins identified as potential drug targets is increasing exponentially as scientists make progress in the fields of genomics and proteomics, but with current methods, scientists have successfully obtained useful crystals for less than 20 per cent of proteins that have been tried.
The researchers developed “molecularly imprinted polymers” (MIPs), compounds made up of small units that bind together around the outside of a molecule. When the molecule is extracted, it leaves a cavity that retains its shape and has a strong affinity for the target molecule. This property makes MIPs ideal nucleants (substances that bind protein molecules and make it easier for them to come together to form crystals).
The researchers found that six different MIPs induced crystallization of nine proteins, yielding crystals in conditions that do not give crystals otherwise. They also tested whether MIPs would be effective at producing crystals from a series of preliminary trials for three target proteins for which scientists have not previously been able to obtain crystals of sufficient quality. The presence of MIPs gave rise to crystals in eight to ten percent of such trials, yielding valuable crystals that would have been missed using other known nucleants.
These results should provide insights into new medicines by helping scientists work out the structure of drug targets, the researchers said.
Ref.: Emmanuel Saridakis, et al., Protein crystallization facilitated by molecularly imprinted polymers, PNAS, 2011; [DOI: 10.1073/pnas.1016539108]