Identification of functional and druggable sites in Aspergillus fumigatus essential phosphatases by virtual screening

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Thornton, Benjamin P., Johns, Anna, Al-Shidhani, Reem, Álvarez-Carretero, Sandra, Storer, Isabelle S.R., Bromley, Michael J. and Tabernero, Lydia (2019) Identification of functional and druggable sites in Aspergillus fumigatus essential phosphatases by virtual screening. International Journal of Molecular Sciences, 20 (18). ISSN 1661-6596

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Abstract

Fungal diseases are a serious health burden worldwide with drug resistance compromising efficacy of the limited arsenal of antifungals available. New drugs with novel mechanisms of action are desperately needed to overcome current challenges. The screening of the Aspergillus fumigatus genome identified 35 phosphatases, four of which were previously reported as essential for viability. In addition, we validated another three essential phosphatases. Phosphatases control critical events in fungi from cell wall integrity to cell cycle, thus they are attractive targets for drug development. We used VSpipe v1.0, a virtual screening pipeline, to evaluate the druggability of the seven essential phosphatases and identify starting points for drug discovery. Targeted virtual screening and evaluation of the ligand efficiency plots created by VSpipe, enabled us to define the most favourable chemical space for drug development and suggested different modes of inhibition for each phosphatase. Interestingly, the identified ligand binding sites match with functional sites (active site and protein interaction sites) reported for other yeast and human homologues. Thus, the VSpipe virtual screening approach identified both druggable and functional sites in these essential phosphatases for further experimental validation and antifungal drug development.

Item Type: Article
Additional Information: Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Uncontrolled Keywords: antifungals,aspergillus fumigatus,computational screening,drug discovery,ligand efficiency indices (leis),phosphatase inhibitors,protein phosphatases (ppases),virtual screening (vs),vspipe,catalysis,molecular biology,spectroscopy,computer science applications,physical and theoretical chemistry,organic chemistry,inorganic chemistry ,/dk/atira/pure/subjectarea/asjc/1500/1503
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 19 Aug 2025 14:30
Last Modified: 19 Aug 2025 14:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/100155
DOI: 10.3390/ijms20184636

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