Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors

Deborah E. A. Lockhart, Alexander Schuettelkopf, David E. Blair, Daan M. F. van Aalten (Corresponding Author)

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A limited therapeutic arsenal against increasing clinical disease due to Aspergillus spp. necessitates urgent characterisation of new antifungal targets. Here we describe the discovery of novel, low micromolar chemical inhibitors of Aspergillus fumigatus family 18 plant-type chitinase A1 (AfChiA1) by high-throughput screening (HTS). Analysis of the binding mode by X-ray crystallography confirmed competitive inhibition and kinetic studies revealed two compounds with selectivity towards fungal plant-type chitinases. These inhibitors provide new chemical tools to probe the effects of chitinase inhibition on A. fumigatus growth and virulence, presenting attractive starting points for the development of further potent drug-like molecules.

Original languageEnglish
Pages (from-to)3282-3290
Number of pages9
JournalFEBS Letters
Issue number17
Early online date22 Jul 2014
Publication statusPublished - 25 Aug 2014

Bibliographical note

We wish to thank the Dundee Drug Discovery Unit for access to the diversity set library and the European Synchrotron Radiation Facility, Grenoble, for time at the beamline. This work was supported by a Grant (G0900138) and a Wellcome Trust Senior Research Fellowship (WT087590MA) to D.M.F.v.A. D.E.A.L. is the recipient of a MRC Clinical Research Training Fellowship (G1100430). The structures have been deposited in the Protein Data Bank with accession codes 4TX6 and 4TXE.


  • Aspergillus fumigatus
  • Chitinases
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors
  • High-Throughput Screening Assays
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Journal Article
  • Research Support, Non-U.S. Gov't


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