Case study 1: Lead orientated synthesis
There is now a clear link between the physical properties of drug molecules and their probability of successfully negotiating the development process to produce marketed products. In turn, the properties of final drug molecules are often dependent on those of the initial starting molecule – the “lead”.
Drug discovery programmes that start with a lead molecule with the right molecular properties offer the best starting points for obtaining high quality drug candidates.
Many drug discovery campaigns start by testing many (often hundreds of thousands) of screening compounds in attempt to identify an active lead molecule. Dr Ian Churcher, leader of the GSK screening collection enhancement group, explains a challenge of maintaining a high quality screening collection:
“It is extremely difficult to identify and acquire large numbers of quality, lead-like molecules from current sources. We recently evaluated 4.6 million commercially available compounds, and less than 1% of these molecules had optimal lead-like properties. Worryingly, recent, GSK’s comprehensive analyses of recent synthetic chemistry papers shows that few academic chemists are developing methods that can yield lead-like molecules.”
Adam Nelson and Steve Marsden, from the University of Leeds, are now collaborating with scientists from GSK to identify and develop new methods for preparing diverse lead-like molecules. The EPSRC-funded project was jointly developed to ensure that the methods developed will meet the specific industrial need.
As Adam Nelson, lead researcher from the University, explains:
“Close engagement with GSK has allowed us to design a project that will address a specific problem facing large pharmaceutical companies – it really allowed us to develop a strong case to obtain the resources necessary to deliver the project. As part of the project, GSK will be contributing specialist expertise – for example in computation chemistry – that will allow us to deliver.”
The project is funded by a £533 000 EPSRC grant entitled “Realising Lead-Oriented Synthesis” on which GSK is a named partner.
Case study 2: Addressing the problem of protein aggregation
Increasing numbers of therapeutic agents under development are biotherapeutics: 25-30% of new drug applications in recent years have been for biological entities. To develop a protein that appears effective in the laboratory into a marketable biotherapeutic, several challenges must be overcome. One such bottleneck in biotherapeutic development that commonly occurs is protein aggregation. Tools to predict and prevent protein aggregation are, consequently, keenly sought.
Scientists from the University of Leeds and MedImmune are collaborating on a PhD studentship which aims to investigate the role that transient excursions from the folded functional state of a protein plays in aggregation. These excursions, known as protein dynamics, will be explored by a number of techniques that include NMR, fluorescence and stopped-flow kinetic measurements.
The collaboration with MedImmune ensures the project remains highly relevant to industry, as lead researcher David Brockwell explains. “By collaborating with MedImmune we are gaining access to a range of proteins with different but known aggregation characteristics. This not only enriches the data available to the project, but because the proteins are therapeutic candidates it allows us to understand how our research can be applied to real-life problems in biopharmaceutical companies”.
MedImmune also understands the benefits of collaboration. “In working with the University of Leeds on this project we gain access to expertise from many disciplines which is being focussed on the prediction and prevention of protein aggregation; one of the key obstacles facing the development of biotherapeutics today” says Andrew Buchanan.
The project is fully funded by MedImmune.