Identification of Novel Functional Inhibitors of Acid Sphingomyelinase
Open Access
- 31 August 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (8), e23852
- https://doi.org/10.1371/journal.pone.0023852
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.Keywords
This publication has 129 references indexed in Scilit:
- Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidasesBritish Journal of Pharmacology, 2011
- Gilenya (FTY720) inhibits acid sphingomyelinase by a mechanism similar to tricyclic antidepressantsBiochemical and Biophysical Research Communications, 2011
- Prediction of passive blood–brain partitioning: Straightforward and effective classification models based on in silico derived physicochemical descriptorsJournal of Molecular Graphics and Modelling, 2010
- Deregulation of sphingolipid metabolism in Alzheimer's diseaseNeurobiology of Aging, 2010
- PubChem: a public information system for analyzing bioactivities of small moleculesNucleic Acids Research, 2009
- The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseasesThe FASEB Journal, 2008
- Quantitative modeling of selective lysosomal targeting for drug designEuropean Biophysics Journal, 2008
- Recent advances in the immunobiology of ceramideExperimental and Molecular Pathology, 2007
- Acid sphingomyelinase inhibition suppresses lipopolysaccharide‐mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium‐induced colitis in miceImmunology, 2007
- Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane raftsNature Medicine, 2003