Fragment-based Drug Discovery Platform

The Fragment-based Drug Discovery Platform provides a comprehensive platform for fragment-based drug discovery using solution-state nuclear magnetic resonance (NMR). We support early-stage hit identification and validation through a wide range of biophysical NMR assays, tailored for both academic and industry collaborations.

During its existence the platform expanded experimental portfolio and experience of handling diverse targets of any molecular size and properties. We developed custom screening solutions to achieve best resultsfor every screen.

At the heart of the facility is a 600 MHz Bruker Avance III HD spectrometer equipped with a TCI cryoprobe and a SampleJet automated sample changer, enabling high sensitivity and throughput. Our infrastructure is fully optimized for automated data acquisition and processing, supporting consistent and reproducible screening campaigns.

We offer access to a well-characterized in-house library of approximately 1,500 structurally diverse rule-of-three-compliant fragments, alongside a dedicated subset of 250 fluorinated fragments for ¹⁹F-based screening. These libraries are regularly maintained and QC-checked for solubility, stability, and purity.

Our screening campaigns include both  ligand-observed and  protein-observed  NMR techniques, enabling detection of weak binding interactions with high sensitivity and confidence for every molecular target:

- **Ligand-Observed NMR**: Rapid and highly sensitive assays such as STD (Saturation Transfer Difference), WaterLOGSY, and ¹⁹F NMR are routinely employed for primary screening. These methods allow identification of binders without the need for isotope-labeled protein and are ideal for initial high-throughput screening of fragment libraries.

- **Protein-Observed NMR**: For confirmed hits, smaller proteins and in-depth characterization, we provide protein-detected experiments such as ¹H-¹⁵N HSQC titrations using uniformly  or selectively ¹⁵N-labeled proteins. These methods enable residue-level mapping of binding sites and quantification of affinities, offering valuable structural insights to guide hit expansion and optimization.

The facility runs multiple screening projects per year and provides full support from initial assay design to hit validation and structural follow-up. We work closely with internal Helmholtz research groups, especially Protein Expression and Purification Facility as well as external academic and pharmaceutical partners to accelerate the development of new chemical starting points for therapeutic targets.

With a strong emphasis on quality, automation, and scientific collaboration, the NMR Fragment Screening Facility is a central resource for fragment-based lead discovery at Helmholtz Munich.