In recent years, fragment-based drug discovery (FBDD) is increasingly utilised both in the pharmaceutical industry and in academic settings to help develop new chemical matter targeting protein targets. The Fragment-Screen project aims to develop innovative instrumentation, workflows and experimental and computational methodologies to accelerate the development of new pharmaceuticals using the approach of FBDD.

The project held its kick-off meeting in March 2023 in Frankfurt. Coordinated by Instruct-ERIC, the EU-funded project is made up of a broad consortium of academic institutions and industrial partners.

Harald Schwalbe, Instruct-ERIC Director, said, “I consider the Fragment-Screen project able to transform fragment-based drug discovery. Within this project, we bring together not only Structural Biologists and Medicinal Chemists, but also major European technology organisations, as well as companies in the rapidly growing field of Artificial Intelligence. At the end of the project, the process of drug development will be substantially improved.”

The project brings together top experts in a range of structural biology disciplines, specifically NMR, Cryo-EM, X-ray crystallography, as well as mass spectrometry and artificial intelligence. These fields already have track records in FBDD, and the aim of Fragment-Screen is to build on this existing foundation of knowledge and expertise. Indeed, several compound libraries currently contain 1000s of compounds screened by NMR and X-ray crystallography.

FBDD research has already led to several drug candidates being granted FDA approval, demonstrating the potential effectiveness of the process. Expanding this further has the capacity to be a pivotal opportunity in the medicinal community.

The project is built up of several work packages, each tasked with advancing the field of FBDD in different disciplines. Specifically, X-ray crystallography (led by EMBL), Cryo-EM (Diamond Light Source), NMR (CIRMMP), and mass spectrometry (University of Leeds) will be the foil for collaboration between the most experienced teams in Europe, both industrial and academic. Additionally, a dedicated work package is in place for data management (led by CNB-CSIC), which is a crucial aspect of structural biology research which too often goes under the radar – and is even more important for FBDD and its huge potential outputs.

The final technique-based work package will focus on artificial intelligence. The importance of AI, to provide initial targets for structural determination for other methods, has become much more visible in recent years, especially since the launch of AlphaFold. But how it can expand further in the field of FBDD is still being considered, and the work package led by EU-OPENSCREEN will be central to this new development.

Together with medicinal chemists, structural insight will provide input for exploitation of artificial intelligence methodologies, ultimately to steer hit-to-lead optimisation programs in drug development.

The research infrastructures central to the project are:

• Instruct-ERIC (Coordinator): Structural Biology
• EU-OPENSCREEN ERIC: Chemical Biology
• ELIXIR: Data Resources for Life Science
• ESRF: European Synchrotron
• European Molecular Biology Laboratory (EMBL)
• Diamond Light Source

Additionally, a leading machine learning group SciML and seven industry partners are involved, providing experience and will co-develop instrumentation and procedures with other partners to remove key bottlenecks that appear in the drug discovery process.

These industrial partners include:

• Bruker Biospin GMBH
• Signals
• ARINAX
• Astex Pharmaceuticals
• ALPX SAS
• FEI Electron Optics BV
• IBM Research

Images by Instruct-ERIC