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F2X-Universal and F2X-Entry: Structurally Diverse Compound Libraries for Crystallographic Fragment Screening.

Wollenhaupt J, Metz A, Barthel T, Lima GMA, Heine A, Mueller U, Klebe G, Weiss MS
Structure 28 694-706.e5 (2020)
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Cited: 21 times
EuropePMC logo PMID: 32413289

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.

Reviews citing this publication (2)

  1. A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process. Noske GD, Nakamura AM, Gawriljuk VO, Fernandes RS, Lima GMA, Rosa HVD, Pereira HD, Zeri ACM, Nascimento AFZ, Freire MCLC, Fearon D, Douangamath A, von Delft F, Oliva G, Godoy AS. J Mol Biol 433 167118 (2021)
  2. A snapshot love story: what serial crystallography has done and will do for us. Henkel A, Oberthür D. Acta Crystallogr D Struct Biol 80 563-579 (2024)

Articles citing this publication (19)

  1. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Günther S, Reinke PYA, Fernández-García Y, Lieske J, Lane TJ, Ginn HM, Koua FHM, Ehrt C, Ewert W, Oberthuer D, Yefanov O, Meier S, Lorenzen K, Krichel B, Kopicki JD, Gelisio L, Brehm W, Dunkel I, Seychell B, Gieseler H, Norton-Baker B, Escudero-Pérez B, Domaracky M, Saouane S, Tolstikova A, White TA, Hänle A, Groessler M, Fleckenstein H, Trost F, Galchenkova M, Gevorkov Y, Li C, Awel S, Peck A, Barthelmess M, Schlünzen F, Lourdu Xavier P, Werner N, Andaleeb H, Ullah N, Falke S, Srinivasan V, França BA, Schwinzer M, Brognaro H, Rogers C, Melo D, Zaitseva-Kinneberg JI, Knoska J, Peña-Murillo GE, Mashhour AR, Hennicke V, Fischer P, Hakanpää J, Meyer J, Gribbon P, Ellinger B, Kuzikov M, Wolf M, Beccari AR, Bourenkov G, von Stetten D, Pompidor G, Bento I, Panneerselvam S, Karpics I, Schneider TR, Garcia-Alai MM, Niebling S, Günther C, Schmidt C, Schubert R, Han H, Boger J, Monteiro DCF, Zhang L, Sun X, Pletzer-Zelgert J, Wollenhaupt J, Feiler CG, Weiss MS, Schulz EC, 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 HN, Pearson AR, Betzel C, Meents A. Science 372 642-646 (2021)
  2. Exploring protein hotspots by optimized fragment pharmacophores. Bajusz D, Wade WS, Satała G, Bojarski AJ, Ilaš J, Ebner J, Grebien F, Papp H, Jakab F, Douangamath A, Fearon D, von Delft F, Schuller M, Ahel I, Wakefield A, Vajda S, Gerencsér J, Pallai P, Keserű GM. Nat Commun 12 3201 (2021)
  3. FragMAX: the fragment-screening platform at the MAX IV Laboratory. Lima GMA, Talibov VO, Jagudin E, Sele C, Nyblom M, Knecht W, Logan DT, Sjögren T, Mueller U. Acta Crystallogr D Struct Biol 76 771-777 (2020)
  4. Pre-clustering data sets using cluster4x improves the signal-to-noise ratio of high-throughput crystallography drug-screening analysis. Ginn HM. Acta Crystallogr D Struct Biol 76 1134-1144 (2020)
  5. Combining High-Throughput Synthesis and High-Throughput Protein Crystallography for Accelerated Hit Identification. Sutanto F, Shaabani S, Oerlemans R, Eris D, Patil P, Hadian M, Wang M, Sharpe ME, Groves MR, Dömling A. Angew Chem Int Ed Engl 60 18231-18239 (2021)
  6. Probing ligand binding of endothiapepsin by `temperature-resolved' macromolecular crystallography. Huang CY, Aumonier S, Engilberge S, Eris D, Smith KML, Leonarski F, Wojdyla JA, Beale JH, Buntschu D, Pauluhn A, Sharpe ME, Metz A, Olieric V, Wang M. Acta Crystallogr D Struct Biol 78 964-974 (2022)
  7. Fragment Libraries Designed to Be Functionally Diverse Recover Protein Binding Information More Efficiently Than Standard Structurally Diverse Libraries. Carbery A, Skyner R, von Delft F, Deane CM. J Med Chem 65 11404-11413 (2022)
  8. Fast fragment- and compound-screening pipeline at the Swiss Light Source. Kaminski JW, Vera L, Stegmann DP, Vering J, Eris D, Smith KML, Huang CY, Meier N, Steuber J, Wang M, Fritz G, Wojdyla JA, Sharpe ME. Acta Crystallogr D Struct Biol 78 328-336 (2022)
  9. Frag4Lead: growing crystallographic fragment hits by catalog using fragment-guided template docking. Metz A, Wollenhaupt J, Glöckner S, Messini N, Huber S, Barthel T, Merabet A, Gerber HD, Heine A, Klebe G, Weiss MS. Acta Crystallogr D Struct Biol 77 1168-1182 (2021)
  10. FragMAXapp: crystallographic fragment-screening data-analysis and project-management system. Lima GMA, Jagudin E, Talibov VO, Benz LS, Marullo C, Barthel T, Wollenhaupt J, Weiss MS, Mueller U. Acta Crystallogr D Struct Biol 77 799-808 (2021)
  11. Letter Of problems and opportunities-How to treat and how to not treat crystallographic fragment screening data. Weiss MS, Wollenhaupt J, Correy GJ, Fraser JS, Heine A, Klebe G, Krojer T, Thunissen M, Pearce NM. Protein Sci 31 e4391 (2022)
  12. Facilitated crystal handling using a simple device for evaporation reduction in microtiter plates. Barthel T, Huschmann FU, Wallacher D, Feiler CG, Klebe G, Weiss MS, Wollenhaupt J. J Appl Crystallogr 54 376-382 (2021)
  13. Fragment-based screening targeting an open form of the SARS-CoV-2 main protease binding pocket. Huang CY, Metz A, Lange R, Artico N, Potot C, Hazemann J, Müller M, Dos Santos M, Chambovey A, Ritz D, Eris D, Meyer S, Bourquin G, Sharpe M, Mac Sweeney A. Acta Crystallogr D Struct Biol 80 123-136 (2024)
  14. Crystallographic fragment screen of the c-di-AMP-synthesizing enzyme CdaA from Bacillus subtilis. Garbers T, Neumann P, Wollenhaupt J, Dickmanns A, Weiss MS, Ficner R. Acta Crystallogr F Struct Biol Commun 80 200-209 (2024)
  15. Crystallographic fragment-binding studies of the Mycobacterium tuberculosis trifunctional enzyme suggest binding pockets for the tails of the acyl-CoA substrates at its active sites and a potential substrate-channeling path between them. Dalwani S, Metz A, Huschmann FU, Weiss MS, Wierenga RK, Venkatesan R. Acta Crystallogr D Struct Biol 80 605-619 (2024)
  16. Design, quality and validation of the EU-OPENSCREEN fragment library poised to a high-throughput screening collection. Jalencas X, Berg H, Espeland LO, Sreeramulu S, Kinnen F, Richter C, Georgiou C, Yadrykhinsky V, Specker E, Jaudzems K, Miletić T, Harmel R, Gribbon P, Schwalbe H, Brenk R, Jirgensons A, Zaliani A, Mestres J. RSC Med Chem 15 1176-1188 (2024)
  17. HEIDI: an experiment-management platform enabling high-throughput fragment and compound screening. Metz A, Stegmann DP, Panepucci EH, Buehlmann S, Huang CY, McAuley KE, Wang M, Wojdyla JA, Sharpe ME, Smith KML. Acta Crystallogr D Struct Biol 80 328-335 (2024)
  18. Mining the Protein Data Bank to inspire fragment library design. Revillo Imbernon J, Chiesa L, Kellenberger E. Front Chem 11 1089714 (2023)
  19. Novel starting points for fragment-based drug design against mycobacterial thioredoxin reductase identified using crystallographic fragment screening. Füsser FT, Wollenhaupt J, Weiss MS, Kümmel D, Koch O. Acta Crystallogr D Struct Biol 79 857-865 (2023)


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