A new $5.3 million facility is making it easier to apply molecular imaging technology to improve the success rate of drug development.

During drug development, pharmaceutical companies routinely screen several million random chemicals. While the number of compounds tested sounds impressive, the industry has long known that it amounts to a tiny fraction of all possible chemical diversity, a situation that tends to cause low drug-discovery rates.

To gain more mileage from less effort, a more targeted approach, called ‘fragment-based drug design’, has been devised and is now available to Australian biotechnology companies through the Bio21 Collaborative Crystallisation Centre at CSIRO’s Parkville facilities in Melbourne.

The Bio21 Centre has recruited two scientists, Dr Janet Newman and Dr Tom Peat, who were among the first in the world to establish the high-throughput crystallography platforms needed to ‘fragment screen’.

“The idea of having a big compound library and doing massive, automated screening to find that one compound with all the right properties is something of a pipedream,” says Dr Peat, explaining the reason pharmaceutical companies in the US and UK have invested in a more targeted strategy.

The new method works with smaller compounds than those traditionally screened. It uses ‘fragments’ of just 10 to 20 atoms. This tactic helps reduce the number of chemical possibilities from a colossal 1060 to a much smaller ‘drug space’ (industry jargon for the chemical universe). That innovation alone allows drug companies to test far more chemical diversity, raising the overall likelihood of discovering promising new
compounds. Chemists then step in and attempt to combine the fragments back into compounds large enough to be used as the basis for new drugs.

To further boost the success rate, the new method takes advantage of the fact that most drugs on the market work by binding and inhibiting a target molecule that has a causative role in human disease.

With this came the realisation that drug development could be enhanced by ‘imaging’ the protein of interest, in particular its three-dimensional structure. Dr Peat says that by being able to ‘see’ the chemical space where the drug needs to bind, attempts can then be made to design a suitable compound.

In other words, this new approach takes the conventional ‘randomness’ out of the search for new chemical compounds by identifying specific sites on a protein that can be targeted (or inhibited).

Since proteins are extremely small (in the billionth-of-a-metre scale) they require a specialised technique – X-ray crystallography – to create the 3D image. Indeed, a great deal of the Bio21 Centre’s value is in its crystallisation expertise. The centre has optimised the process with the use of high-throughput robotics.

The crystallisation process is where Dr Newman has lifted the centre’s profile. She is an internationally recognised leader in the development of crystallisation techniques and has incorporated a career’s worth of insights and fail-safes into the Melbourne facility, which she built from scratch and now runs.

As promising lead compounds are identified, the imaging technique initially used to ‘see’ the target is then re-applied to improve the way drug fragments and the target are interacting.

So promising is this new approach that biotechnology companies with protein targets for drug development are already working with CSIRO Molecular and Health Technologies to develop new drugs. Indeed, local biotech company Avexa recently won a grant worth $4.3 million from the Australian Government to use the new approach to screen for new HIV treatments by developing inhibitors to the viral protein integrase, a protein required by HIV to replicate.

With the virus affecting more than 40 million people worldwide, Avexa CEO Dr Julian Chick says the company is excited by the prospect of working collaboratively with CSIRO.

“The collaboration uses the individual and combined expertise of both Avexa and CSIRO in an innovative drug-discovery program,” Dr Chick says. “Moreover, because it is a non-traditional discovery technology, it should yield non-traditional types of drugs: clearly an advantage where novelty is of utmost importance.”

The Bio21 Centre is jointly operated by CSIRO, the Walter and Eliza Hall Institute of Medical Research, St Vincent’s Institute, the Burnet Institute and the Victorian College of Pharmacy (Monash University).

APPLICATION Fragment-based drug design offers biotechnology companies a more efficient way of screening for new drugs.

BENEFIT Fragment screening has become available to Australian companies through the Bio21 Collaborative Crystallisation Centre.

For further information contact:
CSIRO Enquiries
Email: Solve@csiro.au      Web: www.csiro.au
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Last Updated: August 10, 2007
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