title: Identification of novel functional inhibitors of acid sphingomyelinase.
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.
authors: Department of Psychiatry and Psychotherapy, University of Erlangen, Erlangen, Germany. Johannes.Kornhuber@uk-erlangen.de
authors: Johannes
authors: J
authors: Kornhuber
authors: Markus
authors: M
authors: Muehlbacher
authors: Stefan
authors: S
authors: Trapp
authors: Stefanie
authors: S
authors: Pechmann
authors: Astrid
authors: A
authors: Friedl
authors: Martin
authors: M
authors: Reichel
authors: Christiane
authors: C
authors: Mühle
authors: Lothar
authors: L
authors: Terfloth
authors: Teja W
authors: TW
authors: Groemer
authors: Gudrun M
authors: GM
authors: Spitzer
authors: Klaus R
authors: KR
authors: Liedl
authors: Erich
authors: E
authors: Gulbins
authors: Philipp
authors: P
authors: Tripal
mesh_terms: D001688:Biological Products / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000494:pharmacology*; D006801:Humans; D015203:Reproducibility of Results; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D013108:Sphingomyelin Phosphodiesterase