Identification of Functional and Druggable Sites in Aspergillus fumigatus Essential Phosphatases by Virtual Screening.
Int J Mol Sci
; 20(18)2019 Sep 19.
Article
em En
| MEDLINE
| ID: mdl-31546755
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Aspergillus fumigatus
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Software
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Proteínas Fúngicas
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Genoma Fúngico
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Análise de Sequência de DNA
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Monoéster Fosfórico Hidrolases
Tipo de estudo:
Diagnostic_studies
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Screening_studies
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article