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Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX).

Bentley MR, Ilyichova OV, Wang G, Williams ML, Sharma G, Alwan WS, Whitehouse RL, Mohanty B, Scammells PJ, Heras B, Martin JL, Totsika M, Capuano B, Doak BC, Scanlon MJ
J Med Chem 63 6863-6875 (2020)
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Cited: 11 times
EuropePMC logo PMID: 32529824

Abstract

A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate the initial fragment hits, which usually bind with low affinity to their target. Herein, we describe an analysis using X-ray crystallography of a diverse library of compounds prepared using microscale parallel synthesis. This approach yielded an 8-fold increase in affinity and detailed structural information for the resulting complex, providing an efficient and broadly applicable approach to early fragment development.

Reviews citing this publication (4)

  1. Fragment-based drug discovery-the importance of high-quality molecule libraries. Bon M, Bilsland A, Bower J, McAulay K. Mol Oncol 16 3761-3777 (2022)
  2. Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition. Lloyd MD, Yevglevskis M, Nathubhai A, James TD, Threadgill MD, Woodman TJ. Chem Soc Rev 50 5952-5984 (2021)
  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)
  4. Structural bioinformatic analysis of DsbA proteins and their pathogenicity associated substrates. Santos-Martin C, Wang G, Subedi P, Hor L, Totsika M, Paxman JJ, Heras B. Comput Struct Biotechnol J 19 4725-4737 (2021)

Articles citing this publication (7)

  1. 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)
  2. Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures. Baker LM, Aimon A, Murray JB, Surgenor AE, Matassova N, Roughley SD, Collins PM, Krojer T, von Delft F, Hubbard RE. Commun Chem 3 122 (2020)
  3. 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)
  4. Selective Binding of Small Molecules to Vibrio cholerae DsbA Offers a Starting Point for the Design of Novel Antibacterials. Wang G, Mohanty B, Williams ML, Doak BC, Dhouib R, Totsika M, McMahon RM, Sharma G, Zheng D, Bentley MR, Ka-Yan Chin Y, Horne J, Chalmers DK, Heras B, Scanlon MJ. ChemMedChem 17 e202100673 (2022)
  5. Therapeutic and prognostic potential of GPCRs in prostate cancer from multi-omics landscape. Li S, Chen J, Chen X, Yu J, Guo Y, Li M, Pu X. Front Pharmacol 13 997664 (2022)
  6. Fragment screening libraries for the identification of protein hot spots and their minimal binding pharmacophores. Whitehouse RL, Alwan WS, Ilyichova OV, Taylor AJ, Chandrashekaran IR, Mohanty B, Doak BC, Scanlon MJ. RSC Med Chem 14 135-143 (2023)
  7. Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale. Habeshian S, Merz ML, Sangouard G, Mothukuri GK, Schüttel M, Bognár Z, Díaz-Perlas C, Vesin J, Bortoli Chapalay J, Turcatti G, Cendron L, Angelini A, Heinis C. Nat Commun 13 3823 (2022)


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