CFS capability at PROTEROS – key facts
- In-house workflow
- Systematic establishment of crystallization and soaking conditions
- Pilot screening, Go/no-Go decision for full screen
- Specialized high-throughput data processing pipeline
- PROTEROS´ proprietary 480 fragment library
Case Study:
WRN Helicase
Accelerated and fully structure-guided Fragment-to-Hit Development
- High-quality crystallographic fragment screening (∅ 1.6 Å) delivering a 9.4% hit rate
- 5 fragment hits expanded with Chemical Space Docking™ (BioSolveIT) into Enamine REAL space
- 40 compounds synthesized and tested, with 25% structurally validated (X-ray structures in close agreement with docking predictions)
- Second optimization cycle via REAL Space exploration, achieving 19% success rate
- 63 fragment- and ligand-bound crystal structures generated, enabling rich 3D SAR insights
- Best affinity: 64 µM
A fully structure-based workflow enabling the rapid identification of fragment hits and their progression into validated chemical matter.
Two fast make-on-demand design cycles (~5 weeks each) delivered µM binders while continuously expanding the 3D understanding of the binding site.
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Step-wise optimization for the best quality outcome
Target enabled for crystallography
- Apo structure at 2.2-2.7 Å
- Room temperature and 4°C are both suitable for workflow
Robust crystallization & reliable soaking
- Ready for high-throughput crystallization,
diffraction consistently better than ~2.2 Å
- Maximized DMSO concentration for soaking
- DMSO-free setup for sensitive targets
Pilot Screen
- Evaluation of data homogeneity
- Go/no-Go for full campaign
Full CFS campaign
- State-of-the-art handling with Crystal Shifter
- Automated X-ray data collection
- High-Throughput Data Processing Pipeline
- PanDDA Hit Identification
Proteros 480 Fragment Library
Fragment evolution enabled by Crystallography
- All fragments related to synthons of the ultra-large chemical space Enamine REAL (95 billion)
- > 80% expected synthesis success
- Typically 4-6 weeks synthesis time
- µM binder w/o elaborate custom MedChem
Faster and more cost-effective than classical hit growing approaches.
