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Book ; Online ; Thesis: Crystallographic fragment screening - improvement of workflow, tools and procedures, and application for the development of enzyme and protein-protein interaction modulators

Barthel, Tatjana [Verfasser]

2023

Author's details	Tatjana Barthel
Keywords	Naturwissenschaften ; Science
Subject code	sg500
Language	English
Publisher	Freie Universität Berlin
Publishing place	Berlin
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Large-Scale Crystallographic Fragment Screening Expedites Compound Optimization and Identifies Putative Protein-Protein Interaction Sites.

Barthel, Tatjana / Wollenhaupt, Jan / Lima, Gustavo M A / Wahl, Markus C / Weiss, Manfred S

Journal of medicinal chemistry

2022 Volume 65, Issue 21, Page(s) 14630–14641

Abstract: The identification of starting points for compound development is one of the key steps in early-stage drug discovery. Information-rich techniques such as crystallographic fragment screening can potentially increase the efficiency of this step by ... ...

Abstract	The identification of starting points for compound development is one of the key steps in early-stage drug discovery. Information-rich techniques such as crystallographic fragment screening can potentially increase the efficiency of this step by providing the structural information of the binding mode of the ligands in addition to the mere binding information. Here, we present the crystallographic screening of our 1000-plus-compound F2X-Universal Library against the complex of the yeast spliceosomal Prp8 RNaseH-like domain and the snRNP assembly factor Aar2. The observed 269 hits are distributed over 10 distinct binding sites on the surface of the protein-protein complex. Our work shows that hit clusters from large-scale crystallographic fragment screening campaigns identify known interaction sites with other proteins and suggest putative additional interaction sites. Furthermore, the inherent binding pose validation within the hit clusters may accelerate downstream compound optimization.
MeSH term(s)	Crystallography, X-Ray ; Ligands ; Drug Discovery/methods ; Binding Sites ; Proteins ; Protein Binding
Chemical Substances	Ligands ; Proteins
Language	English
Publishing date	2022-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01165
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Article ; Online: Large-scale ratcheting in a bacterial DEAH/RHA-type RNA helicase that modulates antibiotics susceptibility.

Grass, Lena M / Wollenhaupt, Jan / Barthel, Tatjana / Parfentev, Iwan / Urlaub, Henning / Loll, Bernhard / Klauck, Eberhard / Antelmann, Haike / Wahl, Markus C

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 30

Abstract: Many bacteria harbor RNA-dependent nucleoside-triphosphatases of the DEAH/RHA family, whose molecular mechanisms and cellular functions are poorly understood. Here, we show that ... ...

Abstract	Many bacteria harbor RNA-dependent nucleoside-triphosphatases of the DEAH/RHA family, whose molecular mechanisms and cellular functions are poorly understood. Here, we show that the
MeSH term(s)	Adenosine Diphosphate/metabolism ; Anti-Bacterial Agents/pharmacology ; Binding Sites ; Crystallography, X-Ray ; DEAD-box RNA Helicases/chemistry ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; Drug Resistance, Bacterial ; Escherichia coli/drug effects ; Escherichia coli/enzymology ; Escherichia coli/growth & development ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Models, Molecular ; Protein Conformation
Chemical Substances	Anti-Bacterial Agents ; Escherichia coli Proteins ; Adenosine Diphosphate (61D2G4IYVH) ; hrpA protein, E coli (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2021-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2100370118
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Article: Facilitated crystal handling using a simple device for evaporation reduction in microtiter plates.

Barthel, Tatjana / Huschmann, Franziska U / Wallacher, Dirk / Feiler, Christian G / Klebe, Gerhard / Weiss, Manfred S / Wollenhaupt, Jan

Journal of applied crystallography

2021 Volume 54, Issue Pt 1, Page(s) 376–382

Abstract: In the past two decades, most of the steps in a macromolecular crystallography experiment have undergone tremendous development with respect to speed, feasibility and increase of throughput. The part of the experimental workflow that is still a ... ...

Abstract	In the past two decades, most of the steps in a macromolecular crystallography experiment have undergone tremendous development with respect to speed, feasibility and increase of throughput. The part of the experimental workflow that is still a bottleneck, despite significant efforts, involves the manipulation and harvesting of the crystals for the diffraction experiment. Here, a novel low-cost device is presented that functions as a cover for 96-well crystallization plates. This device enables access to the individual experiments one at a time by its movable parts, while minimizing evaporation of all other experiments of the plate. In initial tests, drops of many typically used crystallization cocktails could be successfully protected for up to 6 h. Therefore, the manipulation and harvesting of crystals is straightforward for the experimenter, enabling significantly higher throughput. This is useful for many macromolecular crystallography experiments, especially multi-crystal screening campaigns.
Language	English
Publishing date	2021-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2020879-0
ISSN	1600-5767 ; 0021-8898
ISSN (online)	1600-5767
ISSN	0021-8898
DOI	10.1107/S1600576720016477
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Article ; Online: F2X-Universal and F2X-Entry: Structurally Diverse Compound Libraries for Crystallographic Fragment Screening.

Wollenhaupt, Jan / Metz, Alexander / Barthel, Tatjana / Lima, Gustavo M A / Heine, Andreas / Mueller, Uwe / Klebe, Gerhard / Weiss, Manfred S

Structure (London, England : 1993)

2020 Volume 28, Issue 6, Page(s) 694–706.e5

Abstract: Crystallographic fragment screening (CFS) provides excellent starting points for projects concerned with drug discovery or biochemical tool compound development. One of the fundamental prerequisites for effective CFS is the availability of a versatile ... ...

Abstract	Crystallographic fragment screening (CFS) provides excellent starting points for projects concerned with drug discovery or biochemical tool compound development. One of the fundamental prerequisites for effective CFS is the availability of a versatile fragment library. Here, we report on the assembly of the 1,103-compound F2X-Universal Library and its 96-compound sub-selection, the F2X-Entry Screen. Both represent the available fragment chemistry and are highly diverse in terms of their 3D-pharmacophore variations. Validation of the F2X-Entry Screen in CFS campaigns using endothiapepsin and the Aar2/RNaseH complex yielded hit rates of 30% and 21%, respectively, and revealed versatile binding sites. Dry presentation of the libraries allows CFS campaigns to be carried out with or without the co-solvent DMSO present. Most of the hits in our validation campaigns could be reproduced also in the absence of DMSO. Consequently, CFS can be carried out more efficiently and for a wider range of conditions and targets.
MeSH term(s)	Aspartic Acid Endopeptidases/chemistry ; Aspartic Acid Endopeptidases/metabolism ; Binding Sites ; Crystallography, X-Ray ; Databases, Chemical ; Drug Discovery ; Drug Evaluation, Preclinical ; Models, Molecular ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	Small Molecule Libraries ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Endothia aspartic proteinase (EC 3.4.23.-)
Language	English
Publishing date	2020-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2020.04.019
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Article ; Online: DYW domain structures imply an unusual regulation principle in plant organellar RNA editing catalysis.

Takenaka, Mizuki / Takenaka, Sachi / Barthel, Tatjana / Frink, Brody / Haag, Sascha / Verbitskiy, Daniil / Oldenkott, Bastian / Schallenberg-Rüdinger, Mareike / Feiler, Christian G / Weiss, Manfred S / Palm, Gottfried J / Weber, Gert

Nature catalysis

2021 Volume 4, Issue 6, Page(s) 510–522

Abstract: RNA editosomes selectively deaminate cytidines to uridines in plant organellar transcripts-mostly to restore protein functionality and consequently facilitate mitochondrial and chloroplast function. The RNA editosomal pentatricopeptide repeat proteins ... ...

Abstract	RNA editosomes selectively deaminate cytidines to uridines in plant organellar transcripts-mostly to restore protein functionality and consequently facilitate mitochondrial and chloroplast function. The RNA editosomal pentatricopeptide repeat proteins serve target RNA recognition, whereas the intensively studied DYW domain elicits catalysis. Here we present structures and functional data of a DYW domain in an inactive ground state and activated. DYW domains harbour a cytidine deaminase fold and a C-terminal DYW motif, with catalytic and structural zinc atoms, respectively. A conserved gating domain within the deaminase fold regulates the active site sterically and mechanistically in a process that we termed gated zinc shutter. Based on the structures, an autoinhibited ground state and its activation are cross-validated by RNA editing assays and differential scanning fluorimetry. We anticipate that, in vivo, the framework of an active plant RNA editosome triggers the release of DYW autoinhibition to ensure a controlled and coordinated cytidine deamination playing a key role in mitochondrial and chloroplast homeostasis.
Language	English
Publishing date	2021-06-21
Publishing country	England
Document type	Journal Article
ISSN	2520-1158
ISSN (online)	2520-1158
DOI	10.1038/s41929-021-00633-x
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Article ; Online: FragMAXapp: crystallographic fragment-screening data-analysis and project-management system.

Lima, Gustavo M A / Jagudin, Elmir / Talibov, Vladimir O / Benz, Laila S / Marullo, Costantino / Barthel, Tatjana / Wollenhaupt, Jan / Weiss, Manfred S / Mueller, Uwe

Acta crystallographica. Section D, Structural biology

2021 Volume 77, Issue Pt 6, Page(s) 799–808

Abstract: Crystallographic fragment screening (CFS) has become one of the major techniques for screening compounds in the early stages of drug-discovery projects. Following the advances in automation and throughput at modern macromolecular crystallography ... ...

Abstract	Crystallographic fragment screening (CFS) has become one of the major techniques for screening compounds in the early stages of drug-discovery projects. Following the advances in automation and throughput at modern macromolecular crystallography beamlines, the bottleneck for CFS has shifted from collecting data to organizing and handling the analysis of such projects. The complexity that emerges from the use of multiple methods for processing and refinement and to search for ligands requires an equally sophisticated solution to summarize the output, allowing researchers to focus on the scientific questions instead of on software technicalities. FragMAXapp is the fragment-screening project-management tool designed to handle CFS projects at MAX IV Laboratory. It benefits from the powerful computing infrastructure of large-scale facilities and, as a web application, it is accessible from everywhere.
MeSH term(s)	Data Analysis ; Drug Discovery/methods ; Ligands ; Macromolecular Substances/chemistry ; Models, Molecular ; Proteins/chemistry ; Software
Chemical Substances	Ligands ; Macromolecular Substances ; Proteins
Language	English
Publishing date	2021-05-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S2059798321003818
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Article ; Online: Frag4Lead: growing crystallographic fragment hits by catalog using fragment-guided template docking.

Metz, Alexander / Wollenhaupt, Jan / Glöckner, Steffen / Messini, Niki / Huber, Simon / Barthel, Tatjana / Merabet, Ahmed / Gerber, Hans Dieter / Heine, Andreas / Klebe, Gerhard / Weiss, Manfred S

Acta crystallographica. Section D, Structural biology

2021 Volume 77, Issue Pt 9, Page(s) 1168–1182

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Aspartic Acid Endopeptidases/chemistry ; Aspartic Acid Endopeptidases/metabolism ; Binding Sites ; Catalytic Domain ; Crystallography, X-Ray/methods ; Drug Discovery/methods ; Ligands ; Models, Molecular ; Protein Binding
Chemical Substances	Ligands ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Endothia aspartic proteinase (EC 3.4.23.-)
Language	English
Publishing date	2021-08-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S2059798321008196
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Article ; Online: Targeting the Main Protease (M

Altincekic, Nadide / Jores, Nathalie / Löhr, Frank / Richter, Christian / Ehrhardt, Claus / Blommers, Marcel J J / Berg, Hannes / Öztürk, Sare / Gande, Santosh L / Linhard, Verena / Orts, Julien / Abi Saad, Marie Jose / Bütikofer, Matthias / Kaderli, Janina / Karlsson, B Göran / Brath, Ulrika / Hedenström, Mattias / Gröbner, Gerhard / Sauer, Uwe H /

Perrakis, Anastassis / Langer, Julian / Banci, Lucia / Cantini, Francesca / Fragai, Marco / Grifagni, Deborah / Barthel, Tatjana / Wollenhaupt, Jan / Weiss, Manfred S / Robertson, Angus / Bax, Adriaan / Sreeramulu, Sridhar / Schwalbe, Harald

ACS chemical biology

2024 Volume 19, Issue 2, Page(s) 563–574

Abstract: The main protease ... ...

Abstract	The main protease M
MeSH term(s)	Drug Discovery/methods ; SARS-CoV-2/metabolism ; Catalytic Domain ; Magnetic Resonance Spectroscopy ; Peptide Hydrolases/metabolism ; Protease Inhibitors/metabolism ; Antiviral Agents/pharmacology ; Molecular Docking Simulation
Chemical Substances	Peptide Hydrolases (EC 3.4.-) ; Protease Inhibitors ; Antiviral Agents
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00720
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Article ; Online: Workflow and Tools for Crystallographic Fragment Screening at the Helmholtz-Zentrum Berlin.

Wollenhaupt, Jan / Barthel, Tatjana / Lima, Gustavo M A / Metz, Alexander / Wallacher, Dirk / Jagudin, Elmir / Huschmann, Franziska U / Hauß, Thomas / Feiler, Christian G / Gerlach, Martin / Hellmig, Michael / Förster, Ronald / Steffien, Michael / Heine, Andreas / Klebe, Gerhard / Mueller, Uwe / Weiss, Manfred S

Journal of visualized experiments : JoVE

2021 , Issue 169

Abstract: Fragment screening is a technique that helps to identify promising starting points for ligand design. Given that crystals of the target protein are available and display reproducibly high-resolution X-ray diffraction properties, crystallography is among ... ...

Abstract	Fragment screening is a technique that helps to identify promising starting points for ligand design. Given that crystals of the target protein are available and display reproducibly high-resolution X-ray diffraction properties, crystallography is among the most preferred methods for fragment screening because of its sensitivity. Additionally, it is the only method providing detailed 3D information of the binding mode of the fragment, which is vital for subsequent rational compound evolution. The routine use of the method depends on the availability of suitable fragment libraries, dedicated means to handle large numbers of samples, state-of-the-art synchrotron beamlines for fast diffraction measurements and largely automated solutions for the analysis of the results. Here, the complete practical workflow and the included tools on how to conduct crystallographic fragment screening (CFS) at the Helmholtz-Zentrum Berlin (HZB) are presented. Preceding this workflow, crystal soaking conditions as well as data collection strategies are optimized for reproducible crystallographic experiments. Then, typically in a one to two-day procedure, a 96-membered CFS-focused library provided as dried ready-to-use plates is employed to soak 192 crystals, which are then flash-cooled individually. The final diffraction experiments can be performed within one day at the robot-mounting supported beamlines BL14.1 and BL14.2 at the BESSY II electron storage ring operated by the HZB in Berlin-Adlershof (Germany). Processing of the crystallographic data, refinement of the protein structures, and hit identification is fast and largely automated using specialized software pipelines on dedicated servers, requiring little user input. Using the CFS workflow at the HZB enables routine screening experiments. It increases the chances for successful identification of fragment hits as starting points to develop more potent binders, useful for pharmacological or biochemical applications.
MeSH term(s)	Berlin ; Crystallization ; Crystallography, X-Ray ; Data Collection ; Drug Evaluation, Preclinical ; Ligands ; Proteins/chemistry ; Software ; Synchrotrons ; Workflow
Chemical Substances	Ligands ; Proteins
Language	English
Publishing date	2021-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/62208
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