Identification of Functional and Druggable Sites in Aspergillus fumigatus Essential Phosphatases by Virtual Screening

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.

Molecular epidemiology, in vitro susceptibility and exoenzyme screening of Malassezia clinical isolates

“…Compared with M. globosa, esterase (C4) and esterase lipase (C8) were more abundant, while naphthol-AS-BI-phosphohydrolase was less abundant in M. furfur. Since lipases and proteases are essential for yeast growth, and phosphatases are crucial for cell wall integrity[18,62,65], our results could explain why M. furfur is the main isolate in our district. In summary, our results demonstrate that M. furfur is predominant in HS and PV patients, but M. globosais predominant in MF patients.…”

A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis

“…The application of these plots to PTP drug discovery has been demonstrated in the literature [32,39], and shown to unveil unique opportunities to explore alternative functional sites to the highly conserved active site [29,30]. The NSEI/nBEI plots generated by VSpipe for each targeted docking were used to assess how the LEI profiles of clusters 1, 4, 5 and 6 vary across the KIM-PTPs (Figure 2).…”

“…Computational approaches to find ligand binding sites are widely used because they are fast, cheaper and a good complement to experimental methods. We recently reported the use of the virtual screening tool, VSpipe [29], to effectively identify functional ligand binding sites on PTP1B, including an allosteric inhibitor site, and on fungal phosphatases [30]. The ability of VSpipe to perform rapid blind docking of compound libraries, together with the assessment of the ligand efficiency indices (LEIs) of the ligands [31,32], facilitates a comparison of the chemicalbiological space of binders at different regions, thus guiding the selection of the most druggable sites for compound development.…”

VSpipe-GUI, an Interactive Graphical User Interface for Virtual Screening and Hit Selection

“…Recently, Onyango et al [17] used VSpipe-CLI for in silico identification of new anti-SARS-CoV-2 main protease (M pro ) molecules. Similarly, various studies have used VSpipe-CLI in identifying hit compounds against selected drug targets such as protein tyrosine phosphatases or a fungal methionine synthase [18][19][20][21].…”