Research@StAndrews
 
The University of St Andrews

Research@StAndrews:FullText >
University of St Andrews Research >
University of St Andrews Research >
University of St Andrews Research >

Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/2463
This item has been viewed 1 times in the last year. View Statistics

Files in This Item:

File Description SizeFormat
Loweetal2012Cheminformatics4_2Predicting.pdf921.45 kBAdobe PDFView/Open
Title: Predicting the mechanism of phospholipidosis
Authors: Lowe, Robert
Mussa, Hamse Y.
Nigsch, Florian
Glen, Robert C.
Mitchell, John B. O.
Keywords: QD Chemistry
Issue Date: 26-Jan-2012
Citation: Lowe , 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 .
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.
Version: Publisher PDF
Status: Peer reviewed
URI: http://hdl.handle.net/10023/2463
http://www.jcheminf.com/content/4/1/2
DOI: http://dx.doi.org/10.1186/1758-2946-4-2
ISSN: 1758-2946
Type: Journal article
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.
Appears in Collections:University of St Andrews Research
Chemistry Research
Biomedical Sciences Research Complex (BSRC) Research



This item is protected by original copyright

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

 

DSpace Software Copyright © 2002-2012  Duraspace - Feedback
For help contact: Digital-Repository@st-andrews.ac.uk | Copyright for this page belongs to St Andrews University Library | Terms and Conditions (Cookies)