Domainex — Helping to improve asthma treatments

Pharmaceutical Technology Europe interviews Trevor Perrior, Research Director at Domainex. Domainex is currently collaborating with St George’s University of London and the University of Manchester in the hope of developing a better treatment for asthma. More about this collaboration can be read here.

Q1: In what ways can current asthma treatments be improved upon?
Asthma is a major health problem (there are projected to be more than 100 million sufferers by 2010, and the therapeutic market is estimated to be worth approximately $15 billion) but current therapies only relieve the symptoms of this disease by making the sufferers' breathing easier, or by reducing the allergen-induced inflammation. Our novel treatment is designed to block allergic sensitization, thereby preventing the symptoms occurring and stopping the disease from getting any worse.

Q2: What is so unique about the asthma research programme?
The therapeutic target is a family of enzymatic allergens, known as peptidases, which are produced by house dust mites. It has been known for a long time that exposure to the faecal pellets of dust mites causes allergic reactions in susceptible people. The peptidases produced by dust mites have been shown to cause a wide-range of allergies including asthma, some kinds of rhinitis (runny nose) and dermatitis. These non-human protein targets offer the possibility of designing selective and safe drugs which work by preventing the triggering of the allergic response. We have designed small molecule inhibitors of these peptidases and Clive Robinson’s at St George's team have shown that they are effective in models of the disease. Drugs that work in this way offer the hope of an effective treatment of the underlying disease — including severe asthma, which is still poorly treated.

Q3: Your company will use its LeadBuilder technology to screen and select chemical compounds suitable for rapid progression. Can you tell us more about this technology?LeadBuilder is a proprietary platform technology developed by our scientists. At the beginning of our projects, we use it as a highly cost-effective method for identifying hit compounds for a specific protein target. We also use it to guide the design of further compounds as we progress from hits to leads, and then on to drug candidates. The technology identifies compounds that will bind tightly to the target protein and that also have drug-like chemical, physical and pharmacokinetic properties.

LeadBuilder starts with a virtual database of approximately 10 million compounds, which we triage with proprietary drug-like filters. This gives us a compound set of about a quarter of a million structures that we call 'NICE' — each compound has the properties that one would wish to find in an ideal starting point for drug discovery. We then select a subset of compounds that are specifically aimed at the protein target of interest using information such as an x-ray structure or a homology model of the protein, or the molecular features of any compounds that are known to bind to the target. Sometimes we can get structures of the protein and of some compounds that bind to it, and this makes LeadBuilder even more effective. The number of compounds we select will depend upon our client’s screening capacity, but we typically aim for 500—5,000 compounds.

Q4: What benefits does the technology offer over traditional screening methods?
Traditional screening of random collections of compounds have fairly low hit rates, which vary from target to target, but are typically of the order of 1 in 10,000 compounds. This means that large numbers of compounds — perhaps hundreds of thousands — have to be screened to get a reasonable number of hits, and this is expensive and time-consuming. Moreover, some of the exciting novel targets emerging from cutting-edge biomedical research are unsuitable for high throughput screening for a variety of technical reasons. To make matters worse, the hits from traditional screening are often found to have liabilities (such as toxicity, poor solubility and so on) that make them unattractive starting points for a medicinal chemistry campaign. Since LeadBuilder is a combination of cutting-edge virtual screening and highly pragmatic medicinal chemistry insight, we have found that we consistently get much higher hit rates — across a range of targets — typically in the range of 1–10%. Our much higher hit rate means that far fewer compounds need to be screened to generate a range of options for medicinal chemistry and, of course, our hits are very tractable so they are ideally suited for rapid progression.

Q5: New technology is being increasingly used to aid drug discovery. How has drug discovery technology advanced during the last decade?
Many new technologies have been developed during the last decade including high throughput screening, combinatorial chemistry, fragment-based screening and many others. Each technology was heralded by its champions as the solution to the well-documented decline in the productivity of drug research, but I have to be honest and say that all of these technologies have failed to live up to the early promises made by their devotees. However, what has emerged recently is an understanding of how we can use these technologies in a much more realistic way. We have learnt that there are no 'miracle cures' to the ailments of drug discovery, but there are ways to apply combinations of these technologies in a selective and, more importantly, intelligent way to solve particular problems, to improve the rate of progression of our projects and to reduce the risk of failures in drug development. I believe we will see the benefits of this more pragmatic use of technology during the coming years.

Q6: What led The Wellcome Trust to offer financial support to the research programme?
I think The Wellcome Trust was attracted by the novelty of the approach and its potential to deliver a powerful new paradigm for the treatment of a very prevalent, and potentially highly debilitating, disease. Domainex, St George’s and the University of Manchester have been collaborating on this project for a number of years with smaller amounts of funding from the Trust. It was the invention of a credible lead series of inhibitors and the demonstration by Clive Robinson and his team that these compounds were highly active in disease models that provided a compelling rationale for The Wellcome Trust to support this programme with a very generous grant under the auspices of their Seeding Drug Discovery Initiative.

www.domainex.co.uk