A New Fragment-Based Pharmacophore Virtual Screening Workflow Identifies Potent Inhibitors of SARS-CoV-2 NSP13 Helicase

Jordi Doijen; Jiexiong Xie; Simone Marsili; Trpta Bains; Mandeep Kaur Mann; Pravien Abeywickrema; Nick Van den Broeck; Christian Permann; Thierry Langer; Gökhan Ibis; Charles-Alexandre Mattelaer; Jeremy Harvey; Sebastiaan van Raalte; Roberto Fino; Vineet Pande; Danielle Peeters; Aaron Patrick; Ellen Van Damme; Herman van Vlijmen; Marnix Van Loock; Edgar Jacoby

doi:10.1002/jcc.70201

A New Fragment-Based Pharmacophore Virtual Screening Workflow Identifies Potent Inhibitors of SARS-CoV-2 NSP13 Helicase

Jordi Doijen
, Jiexiong Xie
, Simone Marsili
, Trpta Bains
, Mandeep Kaur Mann
, Pravien Abeywickrema
, Nick Van den Broeck
, Christian Permann
, Thierry Langer
, Gökhan Ibis
, Charles-Alexandre Mattelaer
, Jeremy Harvey
, Sebastiaan van Raalte
, Roberto Fino
, Vineet Pande
, Danielle Peeters
, Aaron Patrick
, Ellen Van Damme
, Herman van Vlijmen
, Marnix Van Loock

Edgar Jacoby

Department für Pharmazeutische Wissenschaften

Veröffentlichungen: Beitrag in Fachzeitschrift › Artikel › Peer Reviewed

Abstract

Herein we report the in silico discovery of 13 novel micromolar potent inhibitors of the SARS-CoV-2 NSP13 helicase validated in cellular antiviral and biophysical ThermoFluor assays. The compounds, discovered using a novel fragment-based pharmacophore virtual screening workflow named FragmentScout, enable the advancement of novel antiviral agents. FragmentScout uses publicly accessible structural data of the SARS-CoV-2 NSP13 helicase, which was previously generated at the Diamond LightSource by XChem high-throughput crystallographic fragment screening. The workflow generates a joint pharmacophore query for each binding site, thereby aggregating the pharmacophore feature information present in each experimental fragment pose. The joint pharmacophore query is then used to search 3D conformational databases using the Inte:ligand LigandScout XT software. The FragmentScout in silico workflow offers a novel tool for identifying micromolar hits from millimolar fragments in fragment-based lead discovery. It is anticipated that this workflow will enhance systematic data mining of the growing collection of XChem datasets.

Originalsprache	Englisch
Aufsatznummer	e70201
Fachzeitschrift	Journal of Computational Chemistry
Jahrgang	46
Ausgabenummer	23
DOIs	https://doi.org/10.1002/jcc.70201
Publikationsstatus	Veröffentlicht - 5 Sept. 2025

Fördermittel

This work was supported by Vlaams Agentschap Innoveren & Ondernemen (VLAIO), Project HBC.2022.0984, Federal funds from the Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA), OTA number HHSO100201700018C, Corona Accelerated R&D in Europe (CARE), Innovative Medicines Initiative 2 Joint Undertaking (JU). The JU receives support from the European Union's Horizon 2020 research and innovation program EFPIA, Bill & Melinda Gates Foundation, Global Health Drug Discovery Institute, and the University of Dundee, 101005077. Funding: The project was funded in parts by (1) Vlaams Agentschap Innoveren & Ondernemen (VLAIO) Project HBC.2022.0984—DynaPhor: Dynamic Pharmacophores for In Silico Hit Identification in Ultra Large Compound Libraries, and (2) Federal funds from the Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA), under OTA number HHSO100201700018C. This study has been executed as part of the Corona Accelerated R&D in Europe (CARE) project. The project has also received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union's Horizon 2020 research and innovation program EFPIA, Bill & Melinda Gates Foundation, Global Health Drug Discovery Institute, and the University of Dundee. The content of this publication only reflects the author's view, and the JU is not responsible for any use that may be made of the information it contains. We want to acknowledge Alex De Groot and Kristien Raeymaekers for chemical QC.

ÖFOS 2012

301207 Pharmazeutische Chemie

Zugriff auf Dokument

10.1002/jcc.70201

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Verknüpfung zur Publikation in Scopus

Zitationsweisen

Doijen, J., Xie, J., Marsili, S., Bains, T., Mann, M. K., Abeywickrema, P., Van den Broeck, N., Permann, C., Langer, T., Ibis, G., Mattelaer, C.-A., Harvey, J., van Raalte, S., Fino, R., Pande, V., Peeters, D., Patrick, A., Van Damme, E., van Vlijmen, H., ... Jacoby, E. (2025). A New Fragment-Based Pharmacophore Virtual Screening Workflow Identifies Potent Inhibitors of SARS-CoV-2 NSP13 Helicase. Journal of Computational Chemistry, 46(23), Artikel e70201. https://doi.org/10.1002/jcc.70201

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title = "A New Fragment-Based Pharmacophore Virtual Screening Workflow Identifies Potent Inhibitors of SARS-CoV-2 NSP13 Helicase",

abstract = "Herein we report the in silico discovery of 13 novel micromolar potent inhibitors of the SARS-CoV-2 NSP13 helicase validated in cellular antiviral and biophysical ThermoFluor assays. The compounds, discovered using a novel fragment-based pharmacophore virtual screening workflow named FragmentScout, enable the advancement of novel antiviral agents. FragmentScout uses publicly accessible structural data of the SARS-CoV-2 NSP13 helicase, which was previously generated at the Diamond LightSource by XChem high-throughput crystallographic fragment screening. The workflow generates a joint pharmacophore query for each binding site, thereby aggregating the pharmacophore feature information present in each experimental fragment pose. The joint pharmacophore query is then used to search 3D conformational databases using the Inte:ligand LigandScout XT software. The FragmentScout in silico workflow offers a novel tool for identifying micromolar hits from millimolar fragments in fragment-based lead discovery. It is anticipated that this workflow will enhance systematic data mining of the growing collection of XChem datasets.",

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Doijen, J, Xie, J, Marsili, S, Bains, T, Mann, MK, Abeywickrema, P, Van den Broeck, N, Permann, C , Langer, T, Ibis, G, Mattelaer, C-A, Harvey, J, van Raalte, S, Fino, R, Pande, V, Peeters, D, Patrick, A, Van Damme, E, van Vlijmen, H, Van Loock, M & Jacoby, E 2025, 'A New Fragment-Based Pharmacophore Virtual Screening Workflow Identifies Potent Inhibitors of SARS-CoV-2 NSP13 Helicase', Journal of Computational Chemistry, Jg. 46, Nr. 23, e70201. https://doi.org/10.1002/jcc.70201

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AU - Langer, Thierry

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AU - Patrick, Aaron

AU - Van Damme, Ellen

AU - van Vlijmen, Herman

AU - Van Loock, Marnix

AU - Jacoby, Edgar

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ER -

A New Fragment-Based Pharmacophore Virtual Screening Workflow Identifies Potent Inhibitors of SARS-CoV-2 NSP13 Helicase

Abstract

Fördermittel

ÖFOS 2012

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