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Thirty years ago, the study began into how very small molecules could have the ability to harness potential power as drug leads. These molecules have the benefit of being able to sample a large chemical space thanks to their small size which ranges from 150 to 300 Da. They were given the name fragments and, since then, seven of these fragments have been developed into FDA-approved clinical compounds.
From Vemurafenib for treatment of late-stage melanoma approved back in 2011, to Capivasertib for treatment of breast cancer that was just approved November 2023, fragment-based drug discovery has grown at an impressive rate and continues to do so. In addition to these seven FDA-approved compounds, fifty are in clinical trials including four in Phase 3.
Fragment-based drug discovery is a multidisciplinary approach that starts with the design of a fragment library all the way to growth of a promising fragment hit. This involves various screening and characterization methods, including a growing contribution by machine learning. But what goes into finding that potential hit compound that can make it all the way to the patients who need it?
In this collection, we want to highlight research that focuses on fragments in drug discovery. Have you found validated fragment hits for a new disease target? Maybe they unlocked an unreported enzyme mechanism? Were you able to develop a method that is useful for fragment-based drug discovery? Perhaps you found a hit that made it to clinical trials? We invite all scientists who work with fragments in the context of drug discovery to submit their interesting fragment stories. We look forward to hearing all about them.
Here we have also highlighted the most recent work on fragments that has been published with us. These include stories of fragment library design and updated screening methods, as well as recently developed approaches for validating, growing, merging, linking and optimizing fragment hits.
Carbohydrate–protein interactions are key for cell–cell and host–pathogen recognition, but their hydrophilic nature makes the development of drug-like inhibitors a challenge. Here, screening of fragment libraries identifies metal-binding pharmacophores as novel scaffolds for the inhibition of Ca2+-dependent carbohydrate–protein interactions.
The AAA+ ATPase p97 protein is thought to be a potential anticancer target, but direct targeting on its ATPase function has not proven to be a successful strategy in clinical trials due to lack of selectivity. Here, the authors use biolayer interferometry-based fragment screening to identify ligands for the development of protein-protein interaction inhibitors by targeting the SHP-motif as a cofactor binding site in the N-domain of p97.
Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.
Peptide fragments derived from the interfaces of protein-protein interactions (PPIs) provide useful templates for designing small molecule PPI inhibitors. Here, the authors utilize the multivalency of an MdmX-binding p53 peptide to develop a weak inhibitor of MdmX into potent Mdm2/MdmX inhibitors.
Fragment-based drug design is an effective approach to identifying potential binders for a given target protein, but accurately capturing changes in affinity associated with a given set of chemical modifications remains challenging. Here, the authors evaluate the use of absolute binding free energy calculations in guiding fragment optimisation decisions, finding that such calculations can usefully guide fragment elaborations to maximise affinity.
Molecular dynamics (MD) simulations play an important role in assessing allosteric effects to assist fragment-based screening, however, fully allosteric modulation remains challenging via standard unbiased MD simulations. Here, the authors develop steered MD simulations combined with a Markov State Modeling protocol to assess certain protein conformations that are important for allosteric binding.
Interleukin-1β is a pro-inflammatory cytokine of medical importance. Here the authors describe the discovery of a low-molecular weight compound that antagonizes hIL-1β function in cells, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.