Stronger foundations for drug discovery Drug development is a long and arduous process. It suffers from a high attrition rate, with many compounds failing at different stages of the drug discovery and development pathway; this also makes it a costly process. In an effort to address these challenges, researchers on the iDESIGN project are aiming to provide better starting points for drug discovery, as Dr Liam Cox explains. There are many
ways to develop a new drug. A traditional approach begins with a detailed understanding of the disease. “In this strategy, you might start by identifying a target, for example a protein, which is associated with the progression of the disease. Designing a small molecule that can interrupt or change the behaviour of the protein might then provide a way of treating the disease. Further modifications to the starting molecule, using an iterative process of testing and structural refinement, are usually required to turn it into a therapeutic that can be used in the clinic,” explains Dr Liam Cox, Reader in Biological Organic Chemistry at the University of Birmingham. This process is arduous, complex and frequently fails. “Failure to achieve an appropriate safety profile or the physicochemical properties that are needed for in vivo efficacy are common causes of a drug candidate failing to reach the clinic,” outlines Dr Cox. An alternative approach to drug development starts with the chemistry. Many pharmaceutical companies possess compound collections – or libraries – stretching into the millions. These collections are screened with the aim of identifying compounds – so-called hits – that display biological activity. “In this approach, a screen will often look for compounds that cause a change in the phenotype, after which biologists will work out how the change arises, hopefully identifying a druggable biological target,” says Dr Cox. A hit compound from this type of screen then provides the basis for a drug discovery programme. “You still need to do a lot of developmental work, for example, to improve bioavailability or safety,” continues Dr Cox. “But if your starting hit is
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The iDESIGN research team.
of a high quality, for example, if it displays drug-like physicochemical properties, it follows that you should have a greater chance of successfully advancing your compound through the various stages of the drug discovery process.”
initial discovery phase to the identification of a candidate, and through the clinical phases of development to the final drug, compounds typically become increasingly threedimensional in character,” says Dr Cox. There are a number of reasons for this. “A molecule that is more three-dimensional in character is often more soluble, which is a key physicochemical property that affects bioavailability,” explains Dr Cox. A further important factor is selectivity and a more three-dimensional compound typically displays better selectivity for its biological target. Many compounds developed using traditional approaches incorporate socalled aromatic structures, which tend to generate relatively flat molecules. “There
If your starting points for drug discovery are high quality, then you will have a greater chance of progressing through the various stages of the drug discovery and
development process. iDESIGN project Identifying better starting points for drug discovery sits at the heart of the iDESIGN project, an EU-funded industrial doctoral training programme bringing together one academic partner from the UK, the University of Birmingham, and two industrial partners, Symeres, based in the Netherlands, and AnalytiCon Discovery, based in Germany. The project is centred around the development of high-quality compound libraries comprising compounds that exhibit a high level of threedimensionality. “As you progress from the
are good reasons why drug compounds incorporate aromatic structures. But the resulting relatively flat structures can cause problems. For example, sub-optimal selectivity can lead to so-called off-target effects,” outlines Dr Cox. “Such a compound is often described as being promiscuous; it is not only operating on the target that you want it to work on, but also interacting with other targets in the body. This can lead to a poor safety profile and dangerous side-effects that can lead to a drug being withdrawn if it ever reaches the clinic.”
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