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High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits.

Schiebel J, Krimmer SG, Röwer K, Knörlein A, Wang X, Park AY, Stieler M, Ehrmann FR, Fu K, Radeva N, Krug M, Huschmann FU, Glöckner S, Weiss MS, Mueller U, Klebe G, Heine A
Structure 24 1398-1409 (2016)
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Cited: 33 times
EuropePMC logo PMID: 27452405

Abstract

Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ∼25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods.

Reviews citing this publication (6)

  1. Current perspectives in fragment-based lead discovery (FBLD). Lamoree B, Hubbard RE. Essays Biochem 61 453-464 (2017)
  2. Application of Fragment-Based Drug Discovery to Versatile Targets. Li Q. Front Mol Biosci 7 180 (2020)
  3. Concepts and Core Principles of Fragment-Based Drug Design. Kirsch P, Hartman AM, Hirsch AKH, Empting M. Molecules 24 (2019)
  4. Protein X-ray Crystallography and Drug Discovery. Maveyraud L, Mourey L. Molecules 25 (2020)
  5. Structural biology data archiving - where we are and what lies ahead. Kleywegt GJ, Velankar S, Patwardhan A. FEBS Lett 592 2153-2167 (2018)
  6. Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer. Lu Y, Yang Y, Zhu G, Zeng H, Fan Y, Guo F, Xu D, Wang B, Chen D, Ge G. Int J Biol Sci 19 3360-3382 (2023)

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  2. Protein Data Bank Japan (PDBj): updated user interfaces, resource description framework, analysis tools for large structures. Kinjo AR, Bekker GJ, Suzuki H, Tsuchiya Y, Kawabata T, Ikegawa Y, Nakamura H. Nucleic Acids Res 45 D282-D288 (2017)
  3. Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes. Schiebel J, Gaspari R, Wulsdorf T, Ngo K, Sohn C, Schrader TE, Cavalli A, Ostermann A, Heine A, Klebe G. Nat Commun 9 3559 (2018)
  4. Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening. Lountos GT, Zhao XZ, Kiselev E, Tropea JE, Needle D, Pommier Y, Burke TR, Waugh DS. Nucleic Acids Res 47 10134-10150 (2019)
  5. On-chip crystallization for serial crystallography experiments and on-chip ligand-binding studies. Lieske J, Cerv M, Kreida S, Komadina D, Fischer J, Barthelmess M, Fischer P, Pakendorf T, Yefanov O, Mariani V, Seine T, Ross BH, Crosas E, Lorbeer O, Burkhardt A, Lane TJ, Guenther S, Bergtholdt J, Schoen S, Törnroth-Horsefield S, Chapman HN, Meents A. IUCrJ 6 714-728 (2019)
  6. Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites. Pearce NM, Bradley AR, Krojer T, Marsden BD, Deane CM, von Delft F. Struct Dyn 4 032104 (2017)
  7. Cytotoxicity and Antimycobacterial Properties of Pyrrolo[1,2-a]quinoline Derivatives: Molecular Target Identification and Molecular Docking Studies. Venugopala KN, Uppar V, Chandrashekharappa S, Abdallah HH, Pillay M, Deb PK, Morsy MA, Aldhubiab BE, Attimarad M, Nair AB, Sreeharsha N, Tratrat C, Yousef Jaber A, Venugopala R, Mailavaram RP, Al-Jaidi BA, Kandeel M, Haroun M, Padmashali B. Antibiotics (Basel) 9 (2020)
  8. A False-Positive Screening Hit in Fragment-Based Lead Discovery: Watch out for the Red Herring. Cramer J, Schiebel J, Wulsdorf T, Grohe K, Najbauer EE, Ehrmann FR, Radeva N, Zitzer N, Linne U, Linser R, Heine A, Klebe G. Angew Chem Int Ed Engl 56 1908-1913 (2017)
  9. A shared vision for macromolecular crystallography over the next five years. Förster A, Schulze-Briese C. Struct Dyn 6 064302 (2019)
  10. 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)
  11. Structural basis for catalysis and substrate specificity of a 3C-like cysteine protease from a mosquito mesonivirus. Kanitz M, Blanck S, Heine A, Gulyaeva AA, Gorbalenya AE, Ziebuhr J, Diederich WE. Virology 533 21-33 (2019)
  12. Binding Adaptation of GS-441524 Diversifies Macro Domains and Downregulates SARS-CoV-2 de-MARylation Capacity. Tsika AC, Gallo A, Fourkiotis NK, Argyriou AI, Sreeramulu S, Löhr F, Rogov VV, Richter C, Linhard V, Gande SL, Altincekic N, Krishnathas R, Elamri I, Schwalbe H, Wollenhaupt J, Weiss MS, Spyroulias GA. J Mol Biol 434 167720 (2022)
  13. Structural and dynamical description of the enzymatic reaction of a phosphohexomutase. Stiers KM, Graham AC, Zhu JS, Jakeman DL, Nix JC, Beamer LJ. Struct Dyn 6 024703 (2019)
  14. A Proof-of-Concept Fragment Screening of a Hit-Validated 96-Compounds Library against Human Carbonic Anhydrase II. Glöckner S, Heine A, Klebe G. Biomolecules 10 (2020)
  15. 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)
  16. 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)
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