Prediction of functional inhibition of acid sphingomyelinase and acid ceramidase

Cationic amphiphilic substances accumulate in lysosomes and can be used to inhibit acid sphingomyelinase (ASM) and acid ceramidase (aCer). The mechanistic basis and substrate specificity for functional inhibition of lysosomal enzymes have not yet been rigorously evaluated. We aimed to develop a quantitative structure-activity relations (QSAR) model in order to specify the physicochemical characteristics of substances capable of functionally inhibiting acid hydrolases. We selected pKa and logP as physicochemical parameters related to lysosomal cumulation. We used substances with a proven effect on ASM activity as a training set (n=39) to define properties of functional inhibitors. Central nervous system (CNS)-active drugs meeting these criterias were tested in cell culture systems for their effect an ASM activity and aCer protein levels. The analysis resulted in an empirically based QSAR model for functional inhibition of these enzymes. We were able to predict functional inhibition of ASM and characterized several FDA-approved drugs as new functional ASM inhibitors.