Identification of novel functional inhibitors of acid sphingomyelinase.

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

doi: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.

Highlights

Acid sphingomyelinase (ASM, EC 3.1.4.12) is a lysosomal glycoprotein that catalyses the hydrolysis of sphingomyelin into ceramide and phosphorylcholine
These enzymes and an existing de novo synthesis pathway are alternative mechanisms for ceramide generation, activation of acid sphingomyelinase (ASM) itself has been proven to be critical for some cellular responses, such as apoptosis induced by reactive oxygen and nitrogen species [3], chemotherapy drugs such as cisplatin [8], bacteria [5], radiation [9] and CD95 [10]
The aims of the present study were (1) to identify more FIASMAs, (2) to further improve the in silico prediction of functional ASM inhibition by developing compact and -interpretable models with high internal consistency, (3) to investigate the relationship between permeation of the blood-brain barrier and functional inhibition of ASM and (4) to study the distribution of FIASMAs across different classes of drugs licensed for medical use in humans

Summary

Introduction

Acid sphingomyelinase (ASM, EC 3.1.4.12) is a lysosomal glycoprotein that catalyses the hydrolysis of sphingomyelin into ceramide and phosphorylcholine. In turn, leads to membrane reorganization and downstream signalling that results in cell activation, very often cell stress or apoptosis. In addition to ASM, at least three other sphingomyelinases have been described in mammalian cells that vary in their pH optimum and cofactor dependency. These enzymes and an existing de novo synthesis pathway are alternative mechanisms for ceramide generation, activation of ASM itself has been proven to be critical for some cellular responses, such as apoptosis induced by reactive oxygen and nitrogen species [3], chemotherapy drugs such as cisplatin [8], bacteria [5], radiation [9] and CD95 [10]. In contrast to other sphingomyelinases, ASM activity is tightly regulated [11]

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Results