- ◇ STRUCTURAL BIOLOGY · 07
FRAGMENT HITS VIA
Crystallographic Screening
Label-free analysis of molecular mass, oligomeric state and complex formation.
- FRAG · XRD · 1.5 – 2.5 Å
Fragment hits in 96-well plates.
Crystallographic fragment screening — also known as FBLD (Fragment-Based Lead Discovery) by X-ray — is the most direct method for identifying low-affinity binders across a protein binding site. By soaking or co-crystallising a reproducible crystal form with a fragment library and collecting data at a synchrotron, we can detect binding events at millimolar affinities that are invisible to biophysical assays.
Our fragment screening workflow uses PanDDA (Pan-Dataset Density Analysis) to identify weak but consistent electron density signals across hundreds of datasets — a computational approach that dramatically increases hit detection sensitivity by separating true binder signals from crystal-to-crystal noise.
Crystallographic fragment hits deliver immediate structural information on binding mode, vector direction, and pocket geometry — enabling rapid hypothesis generation for medicinal chemistry without further structural experiments.
- ◇ WHAT IT ENABLES
Binding mode and pocket geometry for every hit — at atomic resolution.
Every crystallographic fragment hit delivers a bound structure — showing exactly where the fragment binds, which residues it contacts, and which vectors point toward pocket extension. This information is unavailable from biophysical screens and directly enables structure-guided medicinal chemistry.
PanDDA event maps reveal weak binding events (KD > 1 mM) that are invisible in conventional difference Fourier maps, dramatically increasing hit rates compared to standard soaking campaigns and recovering binders to cryptic or allosteric sites.
- Atomic-resolution binding mode for every hit — no secondary structural experiments needed
- Detection of millimolar binders using PanDDA multi-dataset analysis
- Identification of cryptic and allosteric binding sites not visible in apo structures
- Immediate vector and pharmacophore information for medicinal chemistry follow-up
- ◇ WORKFLOW
How we work.
- 01
Crystal System Validation
Confirmation of reproducible, soakable crystal form with full diffraction data collection.
- 02
Fragment Library Soaking
Compound soaking across DSi-Poised or custom fragment library (300–1000 compounds) in 96-well format.
- 03
Synchrotron Data Collection
High-throughput automated data collection at Diamond I04-1 or ESRF ID23.
- 04
Data Processing
Automated processing of all datasets with XDS and AIMLESS for rapid structure solution.
- 05
PanDDA Analysis
Multi-dataset PanDDA analysis to identify weak binding events and generate event maps for all hits.
- 06
Hit Reporting
Structural hit report with bound coordinates, electron density, and medicinal chemistry annotations.
- 01
Crystal System Validation
Confirmation of reproducible, soakable crystal form with full diffraction data collection.
- 02
Fragment Library Soaking
Compound soaking across DSi-Poised or custom fragment library (300–1000 compounds) in 96-well format.
- 03
Synchrotron Data Collection
High-throughput automated data collection at Diamond I04-1 or ESRF ID23.
- 04
Data Processing
Automated processing of all datasets with XDS and AIMLESS for rapid structure solution.
- 05
PanDDA Analysis
Multi-dataset PanDDA analysis to identify weak binding events and generate event maps for all hits.
- 06
Hit Reporting
Structural hit report with bound coordinates, electron density, and medicinal chemistry annotations.
- ◇ APPLICATIONS
Where this service applies.
Explore how this service is used to address real structural biology challenges across drug discovery, protein engineering, and beyond.
- ◇ FAQ
Fragment screening questions.
What makes a fragment suitable for crystallographic screening?
Fragment libraries typically contain small, chemically diverse compounds designed to explore binding-site chemical space efficiently. Suitability depends on factors such as fragment properties, target compatibility, crystal system, and the screening strategy. BIMOVIS can help define an appropriate screening approach based on the target and project objectives.
How large does a protein crystal need to be for fragment screening?
The required crystal size depends on the target, crystal system, diffraction quality, and data collection strategy. More important than size alone are crystal stability, reproducibility, diffraction quality, and the accessibility of potential binding sites. These factors are assessed during project planning and crystal optimization.
What is the difference between fragment soaking and co-crystallization?
In fragment soaking, pre-formed protein crystals are exposed to fragment compounds before diffraction data collection. In co-crystallization, fragments are introduced during protein crystallization so that the complex forms as the crystal grows. The appropriate approach depends on the target, crystal properties, and fragment-binding behavior.
How are fragment hits evaluated after a crystallographic screen?
Potential hits are identified by examining electron density and assessing whether the observed fragment placement is consistent with the experimental data. Hits can then be evaluated based on binding-site location, interaction geometry, chemical tractability, reproducibility, and potential for fragment growing, merging, or linking.
What happens after a fragment hit is identified?
Once a fragment hit is confirmed and its binding mode is understood, the structure can guide follow-up strategies such as fragment growing, merging, or linking. Depending on the project, BIMOVIS can also support additional structural analysis, computational approaches, or experimental validation to evaluate the most promising design directions.
- ◇ RESOURCES & DOWNLOADS
Go deeper in our Knowledge Hub.
Guides, protocols, and reference materials to support your structural biology projects — free to access.