Identification of Novel Functional Inhibitors of Acid Sphingomyelinase
| Autor: | Stefanie Pechmann, Philipp Tripal, Lothar Terfloth, Teja W. Groemer, Johannes Kornhuber, Stefan Trapp, Christiane Mühle, Markus Muehlbacher, Erich Gulbins, Martin Reichel, Astrid Friedl, Gudrun M. Spitzer, Klaus R. Liedl |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Medizin
Sphingomyelin phosphodiesterase Biochemistry Toxicology User-Computer Interface 0302 clinical medicine Drug Discovery Neurobiology of Disease and Regeneration Theoretical Pharmacology Enzyme Inhibitors 0303 health sciences Multidisciplinary Chemistry Drug Information 3. Good health medicine.anatomical_structure Sphingomyelin Phosphodiesterase Blood-Brain Barrier Medicine Acid sphingomyelinase medicine.drug Research Article Biotechnology Drugs and Devices Drug Research and Development Science Medizinische Fakultät -ohne weitere Spezifikation Blood–brain barrier Inhibitory postsynaptic potential 03 medical and health sciences Cell Line Tumor medicine Residual activity Distribution (pharmacology) Humans ddc:610 Protein Interactions Biology 030304 developmental biology Virtual screening Biological Products Proteins Reproducibility of Results Lipid Metabolism Metabolism Apoptosis Small Molecules Medicinal Chemistry 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE Kornhuber, J, Muehlbacher, M, Trapp, S, Pechmann, S, Friedl, A, Reichel, M, Muehle, C, Terfloth, L, Groemer, T W, Spitzer, G M, Liedl, K R, Gulbins, E & Tripal, P 2011, ' Identification of Novel Functional Inhibitors of Acid Sphingomyelinase ', P L o S One, vol. 6, no. 8, pp. e23852 . https://doi.org/10.1371/journal.pone.0023852 PLoS ONE, Vol 6, Iss 8, p e23852 (2011) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0023852 |
| Popis: | 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 mu M 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. |
| Databáze: | OpenAIRE |
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