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Fragment-based drug discovery using cryo-EM.

Saur M, Hartshorn MJ, Dong J, Reeks J, Bunkoczi G, Jhoti H, Williams PA
Drug Discov Today 25 485-490 (2020)
Related entries: 6tsh, 6tsk, 6tte, 6ttf, 6tth, 6ttq

Cited: 28 times
EuropePMC logo PMID: 31877353

Abstract

Recent advances in electron cryo-microscopy (cryo-EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system β-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2).

Reviews - 6tti mentioned but not cited (1)

  1. Applications and prospects of cryo-EM in drug discovery. Zhu KF, Yuan C, Du YM, Sun KL, Zhang XK, Vogel H, Jia XD, Gao YZ, Zhang QF, Wang DP, Zhang HW. Mil Med Res 10 10 (2023)

Articles - 6tti mentioned but not cited (1)

  1. ChemEM: Flexible Docking of Small Molecules in Cryo-EM Structures. Sweeney A, Mulvaney T, Maiorca M, Topf M. J Med Chem 67 199-212 (2024)


Reviews citing this publication (14)

  1. Current strategies for the design of PROTAC linkers: a critical review. Troup RI, Fallan C, Baud MGJ. Explor Target Antitumor Ther 1 273-312 (2020)
  2. Computational approaches streamlining drug discovery. Sadybekov AV, Katritch V. Nature 616 673-685 (2023)
  3. Fragment-to-Lead Medicinal Chemistry Publications in 2020. de Esch IJP, Erlanson DA, Jahnke W, Johnson CN, Walsh L. J Med Chem 65 84-99 (2022)
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  5. Drug discovery in the era of cryo-electron microscopy. Robertson MJ, Meyerowitz JG, Skiniotis G. Trends Biochem Sci 47 124-135 (2022)
  6. Discovery of allosteric binding sites by crystallographic fragment screening. Krojer T, Fraser JS, von Delft F. Curr Opin Struct Biol 65 209-216 (2020)
  7. Changes in Membrane Protein Structural Biology. Birch J, Cheruvara H, Gamage N, Harrison PJ, Lithgo R, Quigley A. Biology (Basel) 9 E401 (2020)
  8. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)
  9. Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics. Jednačak T, Mikulandra I, Novak P. Int J Mol Sci 21 E7799 (2020)
  10. Fragment-Based Drug Discovery against Mycobacteria: The Success and Challenges. Togre NS, Vargas AM, Bhargavi G, Mallakuntla MK, Tiwari S. Int J Mol Sci 23 10669 (2022)
  11. The Knowns and Unknowns in Protein-Metabolite Interactions. Kurbatov I, Dolgalev G, Arzumanian V, Kiseleva O, Poverennaya E. Int J Mol Sci 24 4155 (2023)
  12. E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology. Michaelides IN, Collie GW. J Med Chem 66 3173-3194 (2023)
  13. Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics. Arar S, Haque MA, Kayed R. Proteins (2023)
  14. Cryo-electron microscopy-based drug design. Cebi E, Lee J, Subramani VK, Bak N, Oh C, Kim KK. Front Mol Biosci 11 1342179 (2024)

Articles citing this publication (12)

  1. Cryo-EM with sub-1 Å specimen movement. Naydenova K, Jia P, Russo CJ. Science 370 223-226 (2020)
  2. Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response. Wilson DM, Deacon AM, Duncton MAJ, Pellicena P, Georgiadis MM, Yeh AP, Arvai AS, Moiani D, Tainer JA, Das D. Prog Biophys Mol Biol 163 130-142 (2021)
  3. Industrial cryo-EM facility setup and management. Sader K, Matadeen R, Castro Hartmann P, Halsan T, Schlichten C. Acta Crystallogr D Struct Biol 76 313-325 (2020)
  4. EMDA: A Python package for Electron Microscopy Data Analysis. Warshamanage R, Yamashita K, Murshudov GN. J Struct Biol 214 107826 (2022)
  5. Microchip-based structure determination of low-molecular weight proteins using cryo-electron microscopy. Casasanta MA, Jonaid GM, Kaylor L, Luqiu WY, Solares MJ, Schroen ML, Dearnaley WJ, Wilson J, Dukes MJ, Kelly DF. Nanoscale 13 7285-7293 (2021)
  6. Exiting the tunnel of uncertainty: crystal soak to validated hit. Martin MP, Noble MEM. Acta Crystallogr D Struct Biol 78 1294-1302 (2022)
  7. It started with a Cys: Spontaneous cysteine modification during cryo-EM grid preparation. Klebl DP, Wang Y, Sobott F, Thompson RF, Muench SP. Front Mol Biosci 9 945772 (2022)
  8. PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes. Swint-Kruse L, Dougherty LL, Page B, Wu T, O'Neil PT, Prasannan CB, Timmons C, Tang Q, Parente DJ, Sreenivasan S, Holyoak T, Fenton AW. Database (Oxford) 2023 baad030 (2023)
  9. Baited reconstruction with 2D template matching for high-resolution structure determination in vitro and in vivo without template bias. Lucas BA, Himes BA, Grigorieff N. Elife 12 RP90486 (2023)
  10. The role of NMR in leveraging dynamics and entropy in drug design. Dubey A, Takeuchi K, Reibarkh M, Arthanari H. J Biomol NMR 74 479-498 (2020)
  11. A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1. Das D, Duncton MAJ, Georgiadis TM, Pellicena P, Clark J, Sobol RW, Georgiadis MM, King-Underwood J, Jobes DV, Chang C, Gao Y, Deacon AM, Wilson DM. Int J Mol Sci 24 16637 (2023)
  12. VitroJet: new features and case studies. Henderikx RJM, Mann D, Domanska A, Dong J, Shahzad S, Lak B, Filopoulou A, Ludig D, Grininger M, Momoh J, Laanto E, Oksanen HM, Bisikalo K, Williams PA, Butcher SJ, Peters PJ, Beulen BWAMM. Acta Crystallogr D Struct Biol 80 232-246 (2024)


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