X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 
main protease

Günther, S.; Reinke, P. Y. A.; Fernández-García, Y.; Lieske, J.; Lane, T. J.; Ginn, H. M.; Koua, F. H. M.; Ehrt, C.; Ewert, W.; Oberthuer, D.; Yefanov, O.; Meier, S.; Lorenzen, K.; Krichel, B.; Kopicki, J.-D.; Gelisio, L.; Brehm, W.; Dunkel, I.; Seychell, B.; Gieseler, H.; Norton-Baker, B.; Escudero-Pérez, B.; Domaracky, M.; Saouane, S.; Tolstikova, A.; White, T. A.; Hänle, A.; Groessler, M.; Fleckenstein, H.; Trost, F.; Galchenkova, M.; Gevorkov, Y.; Li, C.; Awel, S.; Peck, A.; Barthelmess, M.; Schlünzen, F.; Paulraj, L. X.; Werner, N.; Andaleeb, H.; Ullah, N.; Falke, S.; Srinivasan, V.; Franca, B. A.; Schwinzer, M.; Brognaro, H.; Rogers, C.; Melo, D.; Zaitsev-Doyle, J. J.; Knoska, J.; Murillo, G. E. P.; Mashhour, A. R.; Guicking, F.; Hennicke, V.; Fischer, P.; Hakanpää, J.; Meyer, J.; Gribbon, P.; Ellinger, B.; Kuzikov, M.; Wolf, M.; Beccari, A. R.; Bourenkov, G.; von Stetten, D.; Pompidor, G.; Bento, I.; Panneerselvam, S.; Karpics, I.; Schneider, T. R.; Alai, M. M. G.; Niebling, S.; Günther, C.; Schmidt, C.; Schubert, R.; Han, H.; Boger, J.; Monteiro, D. C. F.; Zhang, L.; Sun, X.; Pletzer-Zelgert, J.; Wollenhaupt, J.; Feiler, C. G.; Weiss, M. S.; Schulz, E.-C.; Mehrabi, P.; Karničar, K.; Usenik, A.; Loboda, J.; Tidow, H.; Chari, A.; Hilgenfeld, R.; Uetrecht, C.; Cox, R.; Zaliani, A.; Beck, T.; Rarey, M.; Günther, S.; Turk, D.; Hinrichs, W.; Chapman, H. N.; Pearson, A .R.; Betzel, C.; Meents, A.

doi:10.1126/science.abf7945

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X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Günther, S., Reinke, P. Y. A., Fernández-García, Y., Lieske, J., Lane, T. J., Ginn, H. M., et al. (2021). X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science, 372(6542), 642-646. doi:10.1126/science.abf7945.

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SUPPLEMENT.pdf(Materials and Methods; Supplementary Text; Figs. S1 to S9; Tables S2, S5, and S6; References), TABLE S1.xlsx (Screened drug repurposing libraries. All tested compounds from the "Fraunhofer IME Repurposing Collection" and the "Safe-in-man" library, including information about tested crystals, obtained high-quality datasets and identified hits.), TABLE S4.xlsx (Summary of X-ray crystallographic data processing and refinement statistics), TABLE S7.xlsx (In silico screening of repurposing library against Mpro. The highest ranked 200 compounds of the virtual screening. The names and HYDE scores of the top ranked molecules are given. The yellow background highlights compounds for which high-quality X-ray data was obtained in the X-ray screening. The green background highlights compounds that were detected in the active site in the X-ray screen. Compounds highlighted in light green show a similar binding mode to the fragment with the PDB ligand ID K0G in complex with pro (PDB ID 5R83). Compounds highlighted in light yellow were reported as being active in other screening studies.), TABLE S3.xlsx (Comprehensive summary sheets of hit compounds. Summary showing electron-density maps, compound interactions with Mpro, detailed compound information, biochemical and cell-based antiviral reduction data.), MDAR REPRODUCIBILITY CHECKLIST.pdf

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Creators:
Günther, S.¹, Author
Reinke, P. Y. A.¹, Author
Fernández-García, Y.¹, Author
Lieske, J.¹, Author
Lane, T. J.¹, Author
Ginn, H. M.¹, Author
Koua, F. H. M.¹, Author
Ehrt, C.¹, Author
Ewert, W.¹, Author
Oberthuer, D.¹, Author
Yefanov, O.¹, Author
Meier, S.¹, Author
Lorenzen, K.¹, Author
Krichel, B.¹, Author
Kopicki, J.-D.¹, Author
Gelisio, L.¹, Author
Brehm, W.¹, Author
Dunkel, I.¹, Author
Seychell, B.¹, Author
Gieseler, H.¹, Author
Norton-Baker, B.^{2, 3}, AuthorEscudero-Pérez, B.¹, AuthorDomaracky, M.¹, AuthorSaouane, S.¹, AuthorTolstikova, A.¹, AuthorWhite, T. A.¹, AuthorHänle, A.¹, AuthorGroessler, M.¹, AuthorFleckenstein, H.¹, AuthorTrost, F.¹, AuthorGalchenkova, M.¹, AuthorGevorkov, Y.¹, AuthorLi, C.¹, AuthorAwel, S.¹, AuthorPeck, A.¹, AuthorBarthelmess, M.¹, AuthorSchlünzen, F.¹, AuthorPaulraj, L. X.^{4, 5}, Author Werner, N.¹, AuthorAndaleeb, H.¹, AuthorUllah, N.¹, AuthorFalke, S.¹, AuthorSrinivasan, V.¹, AuthorFranca, B. A.¹, AuthorSchwinzer, M.¹, AuthorBrognaro, H.¹, AuthorRogers, C.¹, AuthorMelo, D.¹, AuthorZaitsev-Doyle, J. J.¹, AuthorKnoska, J.¹, AuthorMurillo, G. E. P.¹, AuthorMashhour, A. R.¹, AuthorGuicking, F.¹, AuthorHennicke, V.¹, AuthorFischer, P.¹, AuthorHakanpää, J.¹, AuthorMeyer, J.¹, AuthorGribbon, P.¹, AuthorEllinger, B.¹, AuthorKuzikov, M.¹, AuthorWolf, M.¹, AuthorBeccari, A. R.¹, AuthorBourenkov, G.¹, Authorvon Stetten, D.¹, AuthorPompidor, G.¹, AuthorBento, I.¹, AuthorPanneerselvam, S.¹, AuthorKarpics, I.¹, AuthorSchneider, T. R.¹, AuthorAlai, M. M. G.¹, AuthorNiebling, S.¹, AuthorGünther, C.¹, AuthorSchmidt, C.¹, AuthorSchubert, R.¹, AuthorHan, H.¹, AuthorBoger, J.¹, AuthorMonteiro, D. C. F.¹, AuthorZhang, L.¹, AuthorSun, X.¹, AuthorPletzer-Zelgert, J.¹, AuthorWollenhaupt, J.¹, AuthorFeiler, C. G.¹, AuthorWeiss, M. S.¹, AuthorSchulz, E.-C.², AuthorMehrabi, P.², AuthorKarničar, K.¹, AuthorUsenik, A.¹, AuthorLoboda, J.¹, AuthorTidow, H.¹, AuthorChari, A.¹, AuthorHilgenfeld, R.¹, AuthorUetrecht, C.¹, AuthorCox, R.¹, AuthorZaliani, A.¹, AuthorBeck, T.¹, AuthorRarey, M.¹, AuthorGünther, S.¹, AuthorTurk, D.¹, AuthorHinrichs, W.¹, AuthorChapman, H. N.¹, AuthorPearson, A .R.¹, AuthorBetzel, C.¹, AuthorMeents, A.¹, Author more..

Affiliations:
1external, ou_persistent22
2Miller Group, Atomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_1938288
3Department of Chemistry, UC Irvine, ou_persistent22
4Center for Free-Electron Laser Science, DESY, ou_persistent22
5International Max Planck Research School for Ultrafast Imaging & Structural Dynamics (IMPRS-UFAST), Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_2266714

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Abstract: The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^pro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^pro. In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

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Language(s): eng - English

Dates: Submitted: 2020-11-20Accepted: 2021-03-29Published Online: 2021-04-02Date issued: 2021-05-07

Publication Status: Issued

Pages: 5

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Table of Contents: -

Rev. Type: Peer

Identifiers: DOI: 10.1126/science.abf7945

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Project name : -

Grant ID : 101003551

Funding program : Horizon 2020 (H2020)

Funding organization : European Commission (EC)

Project name : -

Grant ID : 759661

Funding program : Horizon 2020 (H2020)

Funding organization : European Commission (EC)

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Title: Science

Abbreviation : Science

Source Genre: Journal

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Publ. Info: Washington, D.C. : American Association for the Advancement of Science

Pages: - Volume / Issue: 372 (6542) Sequence Number: - Start / End Page: 642 - 646 Identifier: ISSN: 0036-8075
CoNE: https://pure.mpg.de/cone/journals/resource/991042748276600_1