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Link to original content: https://www.ncbi.nlm.nih.gov/pubmed/21909365
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. 2011;6(8):e23852.
doi: 10.1371/journal.pone.0023852. Epub 2011 Aug 31.

Identification of novel functional inhibitors of acid sphingomyelinase

Johannes Kornhuber  1 , Markus Muehlbacher, Stefan Trapp, Stefanie Pechmann, Astrid Friedl, Martin Reichel, Christiane Mühle, Lothar Terfloth, Teja W Groemer, Gudrun M Spitzer, Klaus R Liedl, Erich Gulbins, Philipp Tripal
Affiliations

Identification of novel functional inhibitors of acid sphingomyelinase

Johannes Kornhuber et al. PLoS One. 2011.

Abstract

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans.

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Conflict of interest statement

Competing Interests: LT is employed by a commercial company (Molecular Networks GmbH, Erlangen, Germany). The authors' employment does not alter their adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1
Figure 1. Analyzed compounds show a bimodal distribution with respect to functional inhibition of ASM.
The histogram includes results of 276 experimentally investigated compounds (see Table S1). The line represents a Gaussian fit to the two peaks.
Figure 2
Figure 2. FIASMAs work in an additive way: The combination of a subthreshold-concentration of amitriptyline 6 and fluoxetine 104 (2.5 µM) results in functional inhibition of ASM.
This effect is also evident at higher concentrations. Mean values ± SD from 3 experiments are given.
Figure 3
Figure 3. Functional inhibition of ASM appears to be associated with good passive diffusion across the blood-brain barrier.
Experimental logBB values were compiled from the literature, with values greater than 0 indicating good blood-brain barrier permeability. Functional inhibition of ASM was experimentally determined in cell culture; residual ASM activity below 50% relative to control cells indicates active compounds. See also results in Table S1.
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