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The UCL School of Pharmacy NMR facility is pleased to offer a fragment screening service designed to identify chemical probes for proteins and other macromolecules.
The 19F fragment screening service has been developed together with the Waudby group (waudbylab.org), providing expert advice for interpreting results and planning follow-up experiments including more detailed binding analyses or structure-activity relationship studies.
What is fragment screening?
Fragment screening identifies small chemical compounds (fragments) that bind to your target molecule, providing starting points for drug discovery. Unlike traditional high-throughput screening, fragment approaches detect weaker but more atom-efficient binding interactions, often revealing novel binding sites and chemotypes that can be elaborated into more potent ligands through medicinal chemistry.
Our fragment library and cocktail approach
We have approximately 450 fragments from the BioNET 19F library1, all of which contain at least one fluorine atom, adhere to the rule of three (MW < 300 Da, cLogP ≤ 3, hydrogen bond donors/acceptors ≤ 3), are soluble in typical biological buffers, and are PAINS-free.
The unique advantage of 19F NMR screening is that we can test many fragments at once because fluorine signals are well-separated in NMR spectra. This allows us to identify which specific compounds are binding to your protein even when mixed together in cocktails of ca. 30 compounds. This approach dramatically accelerates the screening process and significantly reduces the amount of the target macromolecule required.
Our workflow
The screening process follows three steps:
- Sample preparation: Using our Bruker SamplePro Tube liquid handling robot, we prepare reference cocktails in buffer alongside identical samples containing your target macromolecule. This automated approach ensures reproducibility and consistency across all samples.
- Data acquisition: We collect three complementary NMR experiments:
- 1H profiles for quality control of macromolecule integrity and sample pH
- 19F profiles for fragment intensity and chemical shift analysis
- 19F T2 relaxation experiments that detect binding by observing how fragment mobility changes when bound to your target. Even weakly binding fragments tumble more slowly when interacting with the larger macromolecule, providing a sensitive measure of binding.
- Data analysis: You will receive the raw NMR data and access to our user-friendly NMRScreen.jl analysis tool2. This has been developed in-house with medicinal chemists and structural biologists in mind, and makes fragment hit identification straightforward even for those without NMR expertise. The tool automatically matches signals to compounds, calculates binding parameters, and generates clear visualisations of your results.
Sample Requirements
Fragment Screening Buffer
- 50 mL of an aqueous buffer containing 10% D2O
- Recommended composition: 50 mM sodium phosphate, 100 mM sodium chloride, 50 μM 2,2-dimethyl-2-2-silapentane-5-sulfonate (DSS), 10% D2O, pH 7.4. This buffer can be provided upon request at extra cost.
Using our recommended buffer is highly advised where possible as it simplifies analysis. Fragment chemical shifts vary with temperature, pH, and buffer composition. When alternative buffers are used, follow-up experiments may be required to verify the identity of fragments hits.
Target macromolecule
- 2–3 mg target macromolecule typically prepared at 0.5 mg/mL in fragment screening buffer
The target concentration may be adjusted depending on its intrinsic ligand efficiency, i.e. how ‘druggable’ the target is expected to be. We are happy to advise on this.
Contact us to express your interest