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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: 37 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 (7)

  1. Current perspectives in fragment-based lead discovery (FBLD). Lamoree B, Hubbard RE. Essays Biochem 61 453-464 (2017)
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  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)
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  5. 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)
  6. 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)
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  8. 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 E233 (2020)
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  10. EIGER2 hybrid-photon-counting X-ray detectors for advanced synchrotron diffraction experiments. Donath T, Šišak Jung D, Burian M, Radicci V, Zambon P, Fitch AN, Dejoie C, Zhang B, Ruat M, Hanfland M, Kewish CM, van Riessen GA, Naumenko D, Amenitsch H, Bourenkov G, Bricogne G, Chari A, Schulze-Briese C. J Synchrotron Radiat 30 723-738 (2023)
  11. 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)
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