In what I have to admit is now becoming an annual tradition ([2023] [2019]), I’d like to highlight the 2024 edition of the fragment-to-lead success stories, published in J. Med. Chem. at the end of 2025 [Paper].
This year’s publication covers 18 case studies (in line with last year’s 17, but lower than the 10-year average), for a cumulative 233 examples since 2015.
New/On-the-up in 2024
- Membrane proteins: Multiple publications covered efforts to screen membrane proteins with fragments, typically a challenging target class for X-ray crystallography.
- New ligand modalities: Fragments are being used to design PROTACs and molecular glues.
- “Covalent first”: While developing covalent binders from fragment screens isn’t new, the recent surge in screening covalently reactive compounds to identify hit matter, rather than introducing a reactive warhead to a noncovalent starting point, continued.
- Computational methods: While only one virtual screen was reported, most F2L stories included computational design aspects, including one case where FEP was used extensively in the optimisation process.
Key Challenges
- Progressing hits: The authors noted the increasing number of fragment screens being reported with limited/no development of those hits. This is a critical step for which we need more robust, reliable techniques.
Finally, it was great to see the XChem facility at Diamond Light Source be explicitly mentioned.
Citation: Twigg, D.G., Arai, K., Arkin, M.R., Erlanson, D.A., de Esch, I.J., Farkaš, B., Fesik, S.W., Jahnke, W., Johnson, C.N. and Schroeder, M., 2025. Fragment-to-Lead Medicinal Chemistry Publications in 2024: A Tenth Annual Perspective. Journal of Medicinal Chemistry, 68(23), 24830-24847.
