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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: 12 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 (5)

  1. 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)
  2. 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)
  3. Discovery of allosteric binding sites by crystallographic fragment screening. Krojer T, Fraser JS, von Delft F. Curr Opin Struct Biol 65 209-216 (2020)
  4. 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)
  5. 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)



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