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Comprehensive Fragment Screening of the SARS‐CoV‐2 Proteome Explores Novel Chemical Space for Drug Development

Berg, Hannes ; Wirtz Martin, Maria A. ; Altincekic, Nadide ; Alshamleh, Islam ; Kaur Bains, Jasleen ; Blechar, Julius ; Ceylan, Betül ; Jesus, Vanessa de ; Dhamotharan, Karthikeyan ; Fuks, Christin ; Gande, Santosh L. ; Hargittay, Bruno ; Hohmann, Katharina F. ; Hutchison, Marie T. ; Korn, Sophie Marianne ; Krishnathas, Robin ; Kutz, Felicitas ; Linhard, Verena ; Matzel, Tobias ; Meiser, Nathalie ; Niesteruk, Anna ; Pyper, Dennis J. ; Schulte, Linda ; Trucks, Sven ; Azzaoui, Kamal ; Blommers, Marcel J. J. ; Gadiya, Yojana ; Karki, Reagon ; Zaliani, Andrea ; Gribbon, Philip ; Silva Almeida, Marcius da ; Dinis Anobom, Cristiane ; Bula, Anna L. ; Bütikofer, Matthias ; Putinhon Caruso, Ícaro ; Caterina Felli, Isabella ; Da Poian, Andrea T. ; Cardoso de Amorim, Gisele ; Fourkiotis, Nikolaos K. ; Gallo, Angelo ; Ghosh, Dhiman ; Gomes‐Neto, Francisco ; Gorbatyuk, Oksana ; Hao, Bing ; Kurauskas, Vilius ; Lecoq, Lauriane ; Li, Yunfeng ; Cunha Mebus‐Antunes, Nathane ; Mompeán, Miguel ; Cristtina Neves‐Martins, Thais ; Ninot‐Pedrosa, Martí ; Pinheiro, Anderson S. ; Pontoriero, Letizia ; Pustovalova, Yulia ; Riek, Roland ; Robertson, Angus J. ; Jose Abi Saad, Marie ; Treviño, Miguel Á. ; Tsika, Aikaterini C. ; Almeida, Fabio C. L. ; Bax, Ad ; Henzler‐Wildman, Katherine ; Hoch, Jeffrey C. ; Jaudzems, Kristaps ; Laurents, Douglas V. ; Orts, Julien ; Pierattelli, Roberta ; Spyroulias, Georgios A. ; Duchardt‐Ferner, Elke ; Ferner, Jan ; Fürtig, Boris ; Hengesbach, Martin ; Löhr, Frank ; Qureshi, Nusrat ; Richter, Christian ; Saxena, Krishna ; Schlundt, Andreas ; Sreeramulu, Sridhar ; Wacker, Anna ; Weigand, Julia E. ; Wirmer‐Bartoschek, Julia ; Wöhnert, Jens ; Schwalbe, Harald (2024)
Comprehensive Fragment Screening of the SARS‐CoV‐2 Proteome Explores Novel Chemical Space for Drug Development.
In: Angewandte Chemie International Edition, 2022, 61 (46)
doi: 10.26083/tuprints-00022910
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Item Type: Article
Type of entry: Secondary publication
Title: Comprehensive Fragment Screening of the SARS‐CoV‐2 Proteome Explores Novel Chemical Space for Drug Development
Language: English
Date: 22 January 2024
Place of Publication: Darmstadt
Year of primary publication: 2022
Place of primary publication: Weinheim
Publisher: Wiley-VCH
Journal or Publication Title: Angewandte Chemie International Edition
Volume of the journal: 61
Issue Number: 46
Collation: 12 Seiten
DOI: 10.26083/tuprints-00022910
Corresponding Links:
Origin: Secondary publication DeepGreen
Abstract:

SARS‐CoV‐2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti‐virals. Within the international Covid19‐NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR‐detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure‐based drug design against the SCoV2 proteome.

Alternative Abstract:
Alternative AbstractLanguage

Using a fragment-based screening strategy by NMR, we identified 311 small molecule binders of 25 SARS-CoV-2 proteins, thus expanding the previously unexplored chemical and target space. Further, using experimental and bioinformatic analysis we identify potential binding sites. This comprehensive data would greatly assist medicinal chemistry efforts even beyond COVID-19.

English
Uncontrolled Keywords: COVID19-NMR, Drug Discovery, Fragment Screening, NMR Spectroscopy, Protein, SARS-CoV-2
Identification Number: e202205858
Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-229100
Classification DDC: 500 Science and mathematics > 540 Chemistry
500 Science and mathematics > 570 Life sciences, biology
600 Technology, medicine, applied sciences > 610 Medicine and health
Divisions: 10 Department of Biology > RNA Biochemistry
Date Deposited: 22 Jan 2024 13:48
Last Modified: 08 Feb 2024 12:13
SWORD Depositor: Deep Green
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/22910
PPN: 515289604
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