6r49 › Citations

Construction of a Shape-Diverse Fragment Set: Design, Synthesis and Screen against Aurora-A Kinase.

Zhang R, McIntyre PJ, Collins PM, Foley DJ, Arter C, von Delft F, Bayliss R, Warriner S, Nelson A
Chemistry 25 6831-6839 (2019)
Related entries: 6r4a, 6r4b, 6r4c, 6r4d

Cited: 10 times
EuropePMC logo PMID: 31026091

Abstract

Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape-diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3 -rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.

Articles - 6r49 mentioned but not cited (1)

  1. research-article AlphaFold2 models of the active form of all 437 catalytically competent human protein kinase domains. Faezov B, Dunbrack RL. bioRxiv 2023.07.21.550125 (2023)


Reviews citing this publication (2)

  1. Emergent synthetic methods for the modular advancement of sp3-rich fragments. Caplin MJ, Foley DJ. Chem Sci 12 4646-4660 (2021)
  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)

Articles citing this publication (7)

  1. Design and Synthesis of 56 Shape-Diverse 3D Fragments. Downes TD, Jones SP, Klein HF, Wheldon MC, Atobe M, Bond PS, Firth JD, Chan NS, Waddelove L, Hubbard RE, Blakemore DC, De Fusco C, Roughley SD, Vidler LR, Whatton MA, Woolford AJ, Wrigley GL, O'Brien P. Chemistry 26 8969-8975 (2020)
  2. Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains. Johnson JA, Nicolaou CA, Kirberger SE, Pandey AK, Hu H, Pomerantz WCK. ACS Med Chem Lett 10 1648-1654 (2019)
  3. A kinase-independent function for AURORA-A in replisome assembly during DNA replication initiation. Guarino Almeida E, Renaudin X, Venkitaraman AR. Nucleic Acids Res 48 7844-7855 (2020)
  4. Combined Protein- and Ligand-Observed NMR Workflow to Screen Fragment Cocktails against Multiple Proteins: A Case Study Using Bromodomains. Johnson JA, Olson NM, Tooker MJ, Bur SK, Pomerantz WCK. Molecules 25 E3949 (2020)
  5. Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion. Kidd SL, Fowler E, Reinhardt T, Compton T, Mateu N, Newman H, Bellini D, Talon R, McLoughlin J, Krojer T, Aimon A, Bradley A, Fairhead M, Brear P, Díaz-Sáez L, McAuley K, Sore HF, Madin A, O'Donovan DH, Huber KVM, Hyvönen M, von Delft F, Dowson CG, Spring DR. Chem Sci 11 10792-10801 (2020)
  6. In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors. Guo J, Douangamath A, Song W, Coker AR, Chan AWE, Wood SP, Cooper JB, Resnick E, London N, Delft FV. J Struct Biol X 4 100031 (2020)
  7. Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates. Jones SP, Firth JD, Wheldon MC, Atobe M, Hubbard RE, Blakemore DC, De Fusco C, Lucas SCC, Roughley SD, Vidler LR, Whatton MA, Woolford AJ, Wrigley GL, O'Brien P. RSC Med Chem 13 1614-1620 (2022)


Quick links