Back in 2021, I highlighted the annual fragment-to-lead (F2L) success stories from 2019 [Blog post] [Paper]. This is one of my favourite annual publications, and I’m delighted to see that it’s still going strong. In this post, I’ll discuss the 2023 edition that was published in at the start of 2025 [Paper].
17 entries drawn from 16 papers met the F2L bar for 2023 (clear fragment hits, structure/biophysics to confirm binding, and optimisation to potent leads). This is broadly steady with recent years.
What’s (still) working
- Structure-first FBDD continues to dominate: crystallography underpins many campaigns, with orthogonal biophysics the default.
- All main development strategies (growing/merging/linking) are represented. While the majority of F2L examples employ growing or merging, there are some interesting linking examples this year.
- Continued focus on lead efficiency: while a number of papers highighted ways of speeding up the elaboration process, there remains a high focus on ensuring elaboration are efficient (e.g. as measured by ligand efficiency (LE), ligand lipophilicity efficiency (LLE)).
What felt new/more prominent in 2023
- NMR and virtual screening received special mention. Historically fragment-based drug discovery has been relatively unimpacted by computational work compared to other areas so it was great to see this and…
- OPIG tool Fragmenstein [Paper] for fragment merging was highlighed prominently.
- Library design continues to evolve (more diverse, 3D-rich, functionally ready fragments), feeding rapid expansion/optimisation.
Overall, it feels as if the field has continued to mature: output has remained steady, with improved experimental tooling and computational techniques.
If you’re interested in FBDD, take a look!
Citation: Holvey, R. S., Erlanson, D. A., de Esch, I. J., Farkas, B., Jahnke, W., Nishiyama, T., & Woodhead, A. J. (2025). Fragment-to-lead medicinal chemistry publications in 2023. Journal of medicinal chemistry, 68(2), 986-1001.
