Until now, new molecules with the potential to be developed as drugs have been discovered by screening thousands of candidates and developing those showing potential activity in some therapeutic area.
However, this process is extremely expensive and wasteful and the pharmaceutical industry is under increasing pressure to produce more products faster. It is estimated that within the next ten years, for example, pharmaceutical companies will need to market ten times their current output of new products if they are to maintain growth above 10percent.
Now, a potential radical new option couples the unique approach with bioinformation resources. The possibilities of a greater understanding of disease mechanisms which arise from the current explosion of genomics data call for an altogether more rational approach than the trial-and-error method of multiple screening. This project points the way forward for transforming such knowledge into a reasoned search for new drugs.
The new approach was developed as part of the E1.95m, joint UK/French EurekaE2314O’SCREEN project. It promises vastly increased efficiency in drug discovery – testing single, targeted molecules rather than tens of thousands.
The idea is to decide what might be a useful molecular structure – on the basis of genomics or other reasoning – and then to search for a natural plant source using existing databases of plants and their chemical components. Once the compounds of interest have been located, extracted and early-stage tests have confirmed their potential; they can be supplied in a readily-handled form to pharmaceutical companies for further development.
Project co-ordinator Jean-Yves Berthon from French pharmaceuticals company Greentech explains the way this reverse approach developed: “We have a large database of 30000 plants with information on their botany, physiology, chemical components and their applications; also another database on 300000 natural molecules coming from plants. We reasoned that if we had an idea of what molecules would have a particular pharmaceutical effect, we could find a natural source in our databases.”
The method starts with knowledge of key enzymes involved in particular diseases such as acetylcholinesterase in the case of Alzheimer’s disease, tyrosinase for skin pigmentation, or phospholipase A2 for inflammation or asthma.
Development of potential drugs in this way is much faster than using conventional screening.
The project will have a far-reaching effect on the pharmaceutical industry and also on medicine and society in that drug development will be faster and more efficient. It will be possible to reduce the side effects of conventionally-developed drugs – as the potential drug has been designed to achieve a particular change on the enzyme involved in the illness and it is less likely to interact with other systems.
Project team biochemists researched which ligands could be attached to the enzyme to alter its behaviour. Having found the structure to best interact with the enzyme, they then consulted the databases of plants and plant-derived molecules to discover the natural or most closely related sources of this molecule. Identified in this way, substances could then be extracted from the identified plant material and subjected to early-stage testing.
Greentech conducts in vitro and pre-clinical testing as for any pharmaceutical product. But as it is not equipped for further development, the promising compounds are supplied to pharmaceutical companies under licence in an
easy-to-use condition, coated onto microplates ready for further studies and drug substance development. Extracts supplied to other companies for development are often linked with a contract of exclusivity and confidentiality.
The O’SCREEN project did not set out to develop pharmaceuticals, but to develop the methodology of preparing a large and diverse range of natural extracts with real potential for pharmaceutical development by other companies. In order to do that it has refined the databases of plants and their components, extracted and purified most of the natural components, and developed a catalogue of microplates with promising extracts.
Greentech’s partner in the project was Drug Discovery, part of the natural products business of the Strathclyde Institute for Drug Research in Scotland, which has focused on recognition of lead molecules from natural sources for drug development, based on identifying the part of a potential drug molecule responsible for interaction with an enzyme. Its role in the project was to purify, isolate and characterise plant components, to develop the microplate system and to adapt assay kits. Greentech developed relevant bioinformatics tools and services on molecular modelling
The project has been so successful that the project coordinator Greentech has founded a new company (Greenpharma) entirely dedicated to pharmaceutical discovery while Greentech itself has tripled its turnover by applying the technique to developing new, highly effective cosmetic and nutraceutical products.
Greenpharma is as yet only a small company, but it has doubled its turnover in the first two years and is soon hoping to supply licences for drug development in the therapeutic areas of Alzheimer’s disease.
