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dc.contributor.authorLowe, Robert
dc.contributor.authorMussa, Hamse Y.
dc.contributor.authorNigsch, Florian
dc.contributor.authorGlen, Robert C.
dc.contributor.authorMitchell, John B. O.
dc.date.accessioned2012-03-26T23:53:05Z
dc.date.available2012-03-26T23:53:05Z
dc.date.issued2012-01-26
dc.identifier.citationLowe , R , Mussa , H Y , Nigsch , F , Glen , R C & Mitchell , J B O 2012 , ' Predicting the mechanism of phospholipidosis ' , Journal of Cheminformatics , vol. 4 , 2 . https://doi.org/10.1186/1758-2946-4-2en
dc.identifier.issn1758-2946
dc.identifier.otherPURE: 18276128
dc.identifier.otherPURE UUID: 945a51d2-83df-4473-a44d-7b108f9dc3b0
dc.identifier.otherWOS: 000300892200001
dc.identifier.otherScopus: 84862651254
dc.identifier.otherORCID: /0000-0002-0379-6097/work/34033401
dc.identifier.urihttps://hdl.handle.net/10023/2463
dc.description.abstractThe 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.
dc.format.extent9
dc.language.isoeng
dc.relation.ispartofJournal of Cheminformaticsen
dc.rights© 2012 Lowe et al; licensee Chemistry Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en
dc.subjectQD Chemistryen
dc.subject.lccQDen
dc.titlePredicting the mechanism of phospholipidosisen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.identifier.doihttps://doi.org/10.1186/1758-2946-4-2
dc.description.statusPeer revieweden
dc.identifier.urlhttp://www.jcheminf.com/content/4/1/2en


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