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Updated: Aug 29, 2025
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Workflow and Tools for Crystallographic Fragment Screening at the Helmholtz-Zentrum Berlin
Published on: March 3, 2021
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Magnet for the Needle in Haystack: "Crystal Structure First" Fragment Hits Unlock Active Chemical Matter Using
Janis Müller1, Raphael Klein2, Olga Tarkhanova3
1CrystalsFirst GmbH, Marbacher Weg 6, 35037Marburg, Germany.
Journal of Medicinal Chemistry
|September 7, 2022
Summary
This study presents a novel fragment-to-hit approach for drug discovery, identifying active molecules for challenging targets. The method successfully yielded potent binders, bypassing traditional screening limitations.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Drug Discovery
Background:
- Fragment-based drug discovery (FBDD) is effective for challenging targets.
- Existing FBDD methods may miss initial fragment hits.
Purpose of the Study:
- Introduce a novel, multidisciplinary method for identifying active molecules from purchasable chemical space.
- Validate a new fragment-to-hit strategy for drug discovery.
Main Methods:
- Utilized four small-molecule fragment complexes of protein kinase A (PKA).
- Performed template-based docking screens against Enamine's REAL Space.
- Synthesized and validated selected compounds, obtaining crystal structures.
Main Results:
- Synthesized 93 out of 106 selected compounds.
- Identified 40 active compounds, with one showing a 13,500-fold affinity gain.
- Obtained crystal structures for six promising binders, confirming binding modes.
Conclusions:
- Achieved a 40% success rate in a novel fragment-to-hit approach within 9 weeks.
- Demonstrated the potential of this method to identify potent binders for challenging targets.
- Challenged established fragment prescreening paradigms by identifying initial fragments missed by standard assays.
