Open Access Highly Accessed Research article

Predicting the mechanism of phospholipidosis

Robert Lowe1, Hamse Y Mussa1, Florian Nigsch2, Robert C Glen1 and John BO Mitchell3*

Author Affiliations

1 Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

2 Chemical Biology Informatics, Quantitative Biology, Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 220 Massachusetts Avenue, 02139, Cambridge MA, USA

3 Biomedical Sciences Research Complex and EaStCHEM School of Chemistry, Purdie Building, University of St Andrews, North Haugh, St Andrews, Scotland KY16 9ST, UK

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Journal of Cheminformatics 2012, 4:2  doi:10.1186/1758-2946-4-2

Published: 26 January 2012

Abstract

The mechanism of phospholipidosis is still not well understood. Numerous different mechanisms have been proposed, varying from direct inhibition of the breakdown of phospholipids to the binding of a drug compound to the phospholipid, preventing breakdown. We have used a probabilistic method, the Parzen-Rosenblatt Window approach, to build a model from the ChEMBL dataset which can predict from a compound's structure both its primary pharmaceutical target and other targets with which it forms off-target, usually weaker, interactions. Using a small dataset of 182 phospholipidosis-inducing and non-inducing compounds, we predict their off-target activity against targets which could relate to phospholipidosis as a side-effect of a drug. We link these targets to specific mechanisms of inducing this lysosomal build-up of phospholipids in cells. Thus, we show that the induction of phospholipidosis is likely to occur by separate mechanisms when triggered by different cationic amphiphilic drugs. We find that both inhibition of phospholipase activity and enhanced cholesterol biosynthesis are likely to be important mechanisms. Furthermore, we provide evidence suggesting four specific protein targets. Sphingomyelin phosphodiesterase, phospholipase A2 and lysosomal phospholipase A1 are shown to be likely targets for the induction of phospholipidosis by inhibition of phospholipase activity, while lanosterol synthase is predicted to be associated with phospholipidosis being induced by enhanced cholesterol biosynthesis. This analysis provides the impetus for further experimental tests of these hypotheses.

Graphical abstract