Frag4Lead: growing crystallographic fragment hits by catalog using fragment-guided template docking
| Autor: | Andreas Heine, J. Wollenhaupt, Ahmed Merabet, Alexander Metz, Hans Dieter Gerber, Niki Messini, Gerhard Klebe, Steffen Glöckner, T. Barthel, Manfred S. Weiss, Simon Huber |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
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Molecular health care facilities manpower and services Fragment-based lead discovery education Crystallography X-Ray Ligands 01 natural sciences 03 medical and health sciences Structural Biology health services administration Catalytic Domain Drug Discovery Aspartic Acid Endopeptidases Endothiapepsin crystallographic fragment screening fragment based lead discovery template docking structure based drug design pose validation 030304 developmental biology 0303 health sciences Binding Sites biology 010405 organic chemistry Fragment (computer graphics) Chemistry Active site fragment-based lead discovery Isothermal titration calorimetry Small molecule Research Papers 0104 chemical sciences Crystallography Docking (molecular) biology.protein structure-based drug design Target protein Protein Binding |
| Zdroj: | Acta Crystallographica. Section D, Structural Biology Acta Crystallographica Section D Structural Biology |
| ISSN: | 2059-7983 |
| Popis: | A workflow to expand crystallographic fragment hits to higher affinity compounds using readily available analogs is described and successfully applied. In recent years, crystallographic fragment screening has matured into an almost routine experiment at several modern synchrotron sites. The hits of the screening experiment, i.e. small molecules or fragments binding to the target protein, are revealed along with their 3D structural information. Therefore, they can serve as useful starting points for further structure-based hit-to-lead development. However, the progression of fragment hits to tool compounds or even leads is often hampered by a lack of chemical feasibility. As an attractive alternative, compound analogs that embed the fragment hit structurally may be obtained from commercial catalogs. Here, a workflow is reported based on filtering and assessing such potential follow-up compounds by template docking. This means that the crystallographic binding pose was integrated into the docking calculations as a central starting parameter. Subsequently, the candidates are scored on their interactions within the binding pocket. In an initial proof-of-concept study using five starting fragments known to bind to the aspartic protease endothiapepsin, 28 follow-up compounds were selected using the designed workflow and their binding was assessed by crystallography. Ten of these compounds bound to the active site and five of them showed significantly increased affinity in isothermal titration calorimetry of up to single-digit micromolar affinity. Taken together, this strategy is capable of efficiently evolving the initial fragment hits without major synthesis efforts and with full control by X-ray crystallography. |
| Databáze: | OpenAIRE |
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