iDESIGN

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

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.”

The iDESIGN team of chemists are synthesising libraries of high-quality compounds; providing a good starting point can accelerate the drug discovery process and help to reduce the rate of attrition that blights the sector. Dr Cox and his colleagues at Birmingham have developed many bespoke 3D scaffolds during their research; these were shared with their industrial partners at the start of the project who used their medicinal chemistry expertise to identify those that would provide good starting points for drug discovery. These scaffolds typically have two, and sometimes three, decoration sites, which allow researchers to generate a diverse range of compounds. Each compound in a library might derive from a common scaffold but each has a slightly different shape according to how the scaffold has been decorated. “That’s attractive as a starting point for a drug discovery programme because if we identify a hit from a phenotypic screen, then the library of structurally related compounds will allow us to establish quickly a structure-activity relationship to guide further development,” explains Dr Cox.

This also provides important insights into how that molecule is interacting with its target, allowing scientists to generate a pharmacophore, a type of model which defines how a compound interacts with its target and helps the medicinal chemist to develop the initial hit further.

The aim in iDESIGN is to develop libraries of compounds which possess favourable physicochemical properties and are free from structural features and functionality that are known to cause downstream problems in drug development. “If we can get the first stage right, that hopefully means you have to do less work later on,” explains Dr Cox. “Structural modifications are often made to reduce toxicity or metabolism issues. If these problems aren’t there at the start, you can save time and money.”

The scaffolds developed in the iDESIGN project are central to its success. Each researcher has their own project focusing on a particular class of scaffold which has been devised by academics at Birmingham. For example, one PhD student, Daniel Kovari, supervised by Dr Cox and Dr Oliver Kunz from AnalytiCon Discovery, has developed a range of novel spiroacetal scaffolds. “A spiro compound has one atom which is shared by two rings; they are inherently 3D in structure,” explains Dr Cox. In the first half of his project, carried out at Birmingham, Daniel worked closely with his academic supervisor to develop a robust synthetic route to his scaffolds. In January 2020, he transferred to AnalytiCon Discovery where he first synthesised his scaffolds on a large scale. He then worked with his industrial supervisor, Dr Kunz, an expert in compound library design and assembly, to complete his library synthesis. “Colleagues at Birmingham, looking for new treatments of liver disease, recently performed an in silico screen on Daniel’s compound library and identified a small sub-set which appear to interact with their target of interest,” explains Dr Cox. “Daniel has since synthesised these compounds and they have been shipped to Birmingham for physical testing. We’re excited to see if they prove active as they would represent a great starting point for a drug discovery project.”

All six iDESIGN students started their research projects at Birmingham where they also undertook wider training in broader research skills and key transferrable skills. Mid-way through the project, four transferred to Symeres and two to AnalytiCon Discovery to complete their research projects. “The really attractive feature of this type of EU-ITN programme is that it brings together academics and industrialists; each has their particular expertise, which the iDESIGN students have benefited from at the relevant stages of their projects,” explains Dr Cox. Exposing students to these different environments will prepare them for their future careers, whether that lies in academia or in industry. “The project is an industry-academic collaboration, which really helps early-career researchers to understand how science and drug discovery works,” stresses Dr Cox.

A non-traditional view of the University of Birmingham’s clock tower.

Delivering Better Starting Points for Drug Discovery: New Compound Libraries Driven By Intelligent Design Project Objectives

iDESIGN’s Principal Objectives: • to provide a training programme which will train six early-career researchers to become expert synthetic and medicinal chemists, confident research scientists, consummate professionals, effective communicators and innovators with a creative and entrepreneurial spirit. • to use the researchers’ individual PhD projects to develop new, structurally diverse, compound libraries for the pharmaceutical sector to use in hit-identification screening campaigns.

Project Funding

This project is funded by the Horizon2020 European Industrial Doctorate (EID) Innovative Training Network (ITN) ~€1.6M

Contact Details

Project Coordinator, Dr Liam Cox Reader in Biological Organic Chemistry School of Chemistry, University of Birmingham Edgbaston, Birmingham B15 2TT T: +44 (0)121 414 3524 E: l.r.cox@bham.ac.uk W: https://www.birmingham.ac.uk/ research/activity/chemistry/projects/ idesign/idesign.aspx

Dr Liam Cox

Dr Liam Cox is a synthetic organic chemist. He joined the University of Birmingham in 1999 and is currently a Reader in Biological Organic Chemistry. His research focus has shifted increasingly to the interface of chemistry and the life and medical sciences with his team now applying their synthesis skills to solving biological problems and early-stage drug discovery.