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Construction of a shape‐diverse fragment set: Design, synthesis and screen against Aurora‐A kinase

DOI: 10.1002/chem.201900815 DOI Help

Authors: Rong Zhang (University of Leeds) , Patrick J. Mcintyre (University of Leicester) , Patrick M. Collins (Diamond Light Source) , Daniel J. Foley (University of Leeds) , Christopher Arthur (University of Leeds) , Frank Von Delft (Diamond Light Source) , Richard Bayliss (University of Leeds) , Stuart Warriner (University of Leeds) , Adam Nelson (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry – A European Journal , VOL 73

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 14331

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.

Journal Keywords: diversity-oriented synthesis; fragments; molecular shape

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)