Title |
Identification of Novel Functional Inhibitors of Acid Sphingomyelinase
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Published in |
PLOS ONE, August 2011
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DOI | 10.1371/journal.pone.0023852 |
Pubmed ID | |
Authors |
Johannes Kornhuber, 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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 18% |
Unknown | 9 | 82% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 8 | 73% |
Scientists | 2 | 18% |
Science communicators (journalists, bloggers, editors) | 1 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Netherlands | 1 | <1% |
United States | 1 | <1% |
China | 1 | <1% |
Unknown | 156 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 36 | 23% |
Researcher | 36 | 23% |
Student > Bachelor | 20 | 13% |
Student > Master | 16 | 10% |
Student > Doctoral Student | 11 | 7% |
Other | 21 | 13% |
Unknown | 19 | 12% |
Readers by discipline | Count | As % |
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Agricultural and Biological Sciences | 33 | 21% |
Medicine and Dentistry | 21 | 13% |
Biochemistry, Genetics and Molecular Biology | 17 | 11% |
Pharmacology, Toxicology and Pharmaceutical Science | 15 | 9% |
Chemistry | 10 | 6% |
Other | 35 | 22% |
Unknown | 28 | 18% |