Skip to main content

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

Periodic Reporting for period 1 - iDESIGN (Delivering Better Starting Points for Drug Discovery: New Compound Libraries Driven By Intelligent Design)

Reporting period: 2018-01-01 to 2019-12-31

Whilst the need to generate new therapeutics has never been more important, drug discovery is at the same time becoming more difficult. In short, we need to be more efficient at developing drugs. One way of achieving this is to reduce the attrition rates that blight the drug-discovery process.

Drug discovery often begins with a screen of a large compound library to identify a compound, known as a hit, which displays a particular biological ‘readout’ that has been identified to be useful for treating a particular disease. For example, in the search for a new antibiotic, screening a compound library to identify a hit compound that kills the target bacterium, would provide a starting point for further development. In order to maximise our chances of identifying a hit from a compound library, we need to screen a large library of compounds, i.e. library size is important. Compound diversity is also critical; we need to ensure our library is populated with structurally diverse compounds that effectively ‘sample’ as large a volume of available chemical space. Finally, quality is also very important; a library needs to be populated with compounds that possess favourable physicochemical properties that make them conducive to further development.

Traditional compound libraries often display low levels of structural diversity and comprise low-quality compounds that are not conducive to further development; thus, even if a hit is identified from this type of library, the likelihood of it being developed into a drug is low. As a result of the low success rate in developing a hit into a drug, there is a major drive across the pharmaceutical sector to develop compound libraries that are made up of higher quality and structurally diverse molecules that should provide better starting points for drug discovery and development. A principal objective of Project iDESIGN is to use organic chemistry methodology that has been developed by chemists at The University of Birmingham (UK) to develop new and structurally diverse molecular scaffolds, and then to work with our industrial partners, Mercachem (The Netherlands) and AnalytiCon Discovery (Germany) to use these scaffolds as starting points for smart library synthesis.

The pharmaceutical industry also needs a new type of researcher given an increasing proportion of scientists are finding employment in smaller companies, where they need to be more flexible and business-aware. Project iDESIGN seeks to address this particular challenge through a Doctoral Training Programme that combines the complementary expertise from both academic and industrial sectors to train six Early-Stage Researchers to become expert synthetic and medicinal chemists, confident research scientists, consummate professionals, effective communicators and innovators with a creative and entrepreneurial spirit.
iDESIGN started on 1st January 2018. In the first six months, we focused primarily on project set-up and recruitment activities. Communication platforms, including a website and Twitter account, were established in addition to a secure ePortal to allow data and information transfer, sharing and storage between all of the project partners for the duration of the project. A major focus of this first six months of the project involved the recruitment of six Early-Stage Researchers (ESRs). This exercise was led by The University of Birmingham (UK) but also involved our two industrial partners, Mercachem (The Netherlands) and AnalytiCon Discovery (Germany). Six ESRs (male/female ratio: 50/50) from five countries (Belgium, Hungary, Ireland, Italy, Poland) joined the project, as scheduled in September 2018 and registered as PhD students of the University of Birmingham.

In this first phase of the project, our six ESRs successfully completed the vast majority of the training associated with iDESIGN’s four Core Skills Training Programmes (CSTPs). Our CSTPs provide the framework for delivering a diverse range of training to all six ESRs to meet our principal objective of training them to become expert synthetic and medicinal chemists, confident research scientists, consummate professionals, effective communicators and innovators with a creative and entrepreneurial spirit.

Each ESR has a Personal Career Development Plan (PCDP), which was put in place when they joined the project. Our PCDPs help our ESRs to identify specific development needs that might not necessarily be addressed directly or sufficiently through the whole-cohort training programme (CSTPs), and which therefore require personalised or additional attention. Our PCDPs have provided an important mechanism for our ESRs to tailor additional training in order that they are best placed to successfully realise their own career aspirations after completing their PhD programmes.

The ESRs' Personal Research Projects (PRPs) also started in September 2019. In this first phase of their project, the ESRs have developed strong laboratory and molecular synthesis skills and become competent experimentalists. They have used these skills to generate their target molecular scaffolds that will be elaborated into validated compound libraries in the second phase of their projects. The ESRs completed the first phase of their PRPs in December 2019 and moved to their industrial placements in January 2020, where they will focus on compound library synthesis. After 18 months they will return to Birmingham for the final two months of their PhD registration to complete the final stages of their PhD thesis preparation.

The ESRs’ PRPs provide the mechanism by which iDESIGN will achieve its second Principal Objective. Through their research projects, iDESIGN’s ESRs will deliver bespoke compound libraries of structurally and functionally diverse, three-dimensional molecules. These compounds have been designed to possess desirable lead-like physico-chemical properties in order that they provide the best possible starting points for future small-molecule drug discovery. All six ESRs have made good progress on their projects and all have developed robust and scalable synthetic routes to their target scaffolds. They have developed good time-management and planning skills to become efficient and effective experimentalists.
Through their research projects, our six Early-Stage Researchers (ESRs) have collectively assembled a structurally diverse range of scaffolds that are not only novel but also distinctive. In the second phase of their projects, they will decorate these scaffolds to assemble compound libraries. The resulting compounds will not only provide significant added structural diversity to our industry partners' existing compound libraries but as they have also been designed to possess attractive physicochemical properties for future development, such high-quality hits arising from these screens should stand a better chance of being developed successfully into therapeutics for treating a range of diseases. In so doing, project iDESIGN will have a positive impact on the health and well-being of society.
iDesign logo