Skip to main content

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

Periodic Reporting for period 2 - iDESIGN (Delivering Better Starting Points for Drug Discovery: New Compound Libraries Driven By Intelligent Design)

Reporting period: 2020-01-01 to 2021-12-31

The current Covid pandemic reminds us all of the urgent need to develop new treatments for disease. If we are to respond rapidly to new medical emergencies, we need to become more efficient at developing drugs, ideally by reducing the attrition rates that blight drug discovery and development.

Drug discovery often begins with screening a compound library to identify a compound, known as a hit, which displays a biological ‘readout’ that has been identified to be useful for treating a particular disease. For example, in the search for a new antibiotic, a hit compound that kills a target bacterium, would provide a starting point for further development. In order to maximise our chances of identifying a hit, we need to screen a large library of compounds, i.e. 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 as possible. Finally, quality is also 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 often 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 this low success rate, there is a drive across the pharmaceutical sector to develop compound libraries that comprise higher quality and structurally diverse molecules that should provide better starting points for drug discovery and development.

iDESIGN's 1st principal objective was to use methodology developed by chemists at The University of Birmingham (UK), to prepare new and structurally diverse molecular scaffolds, and then, working with our industrial partners at Symeres (The Netherlands) and AnalytiCon Discovery (Germany), use these scaffolds for smart library synthesis. Whilst Covid impacted on the Early-Stage Researchers’ ability to progress their research in the second half of their projects, some re-ordering of work activities ensured they successfully completed their experimental work, culminating in the delivery of new, structurally diverse compound libraries; these have been deposited in our industry partners' compound collections and are now commercially available. A sub-set of compounds were also transferred to The University of Birmingham’s compound collection.

iDESIGN’s 2nd principal objective was to train the appointed Researchers to become expert synthetic and medicinal chemists, confident research scientists, consummate professionals, effective communicators and innovators with a creative and entrepreneurial spirit. Evidencing the success and impact of iDESIGN’s training programme, three of the Researchers are already working in industry, two with the companies they worked for during their industrial placements and the third with Evotec in Verona, Italy. Of the remaining three researchers, two also plan to enter the pharmaceutical industry whilst the third plans to pursue further research in academia as a postdoctoral research fellow before moving into the pharmaceutical sector.
iDESIGN started in Jan. 2018. 6 Early-Stage Researchers (male/female ratio: 3/3) from 5 countries joined the project in Sept. 2018 and registered as PhD students at The University of Birmingham. In the first phase of the project at Birmingham, they successfully completed the majority of their training through four Core Skills Training Programmes. Each Researcher also used a Personal Career Development Plan to tailor additional training to their individual needs and career aspirations. Four Project Workshops focusing on key aspects of early-stage drug discovery, provided further in the second half of the project.

The Researchers developed scaleable synthetic routes to target novel molecular scaffolds in the first stage of their Research Projects. After taking up their Industrial placements in January 2020, they tapped into the expertise of their Industrial Supervisors and open-source software platforms to enumerate compound libraries from each of their validated scaffolds. Workflows were developed to ensure their libraries interrogated a maximal region of drug-like chemical space, considering shape space, key physicochemical property descriptors of direct relevance to small-molecule drug development, and novelty as determined by Tanimoto scoring against commercially available compound libraries.

iDESIGN has generated a new physical collection of 1093 compounds. 333 compounds have already been added to Symeres' compound collection, and 351 compounds have been deposited in AnalytiCon Discovery's collection; these compound libraries are now commercially available. 565 compounds were added to The University of Birmingham’s compound collection, which has already been screened for antimicrobial activity. The enumerated libraries themselves represent a new virtual compound library of 3164 synthetically tractable compounds, which have been deposited in The University of Birmingham’s virtual compound collection and are now available for in silico screening.

Whilst research publications will be forthcoming, we have already used a number of dissemination mechanisms to publicise our project, including a video blog, aimed at encouraging others to consider a career in science and research, an animation directed at a younger audience, and a promotional video, which provides an overview of the iDESIGN project and is aimed at the general public. The Researchers have additionally presented their research in research symposia.
We have amassed a large and diverse physical compound collection that has been experimentally validated and distributed across the 3 Beneficiaries. The collection at Birmingham has recently been screened and excitingly, led to hits against Mycobacteria and a vancomycin-resistant strain of an ESKAPE pathogen, listed as a high-priority target on the WHO priority pathogen list. These hits represent attractive starting points for the development of antimicrobials, and will be a focus for future studies.

A screen of our virtual collection has identified inhibitors of a protein-protein interaction that Birmingham researchers have identified as a target for treating acute alcoholic hepatitis. We have synthesised these compounds and are awaiting the results of physical screening to validate these promising in silico screening studies. This example illustrates the potential of our new virtual collection for identifying hits using computational methods.

iDESIGN has catalysed a significant drive to develop drug discovery activities across The University of Birmingham, with the establishment of a Drug Discovery Hub that brings together researchers from across the University and industry. The project has provided a great opportunity for knowledge transfer; thus, we have exposed our industry colleagues to new synthesis design strategies and encouraged the take up of types of chemistry that have not (yet) received widespread application within industry, whilst for the Academic Beneficiary, working closely with our industry colleagues has helped us to formulate industry-standard criteria for developing our own compound collection.
iDesign logo