Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach

被引：28

作者：

Goracci, Laura ^{[1
]}

Buratta, Sandra ^{[2
]}

Urbanelli, Lorena ^{[2
]}

Ferrara, Giuseppina ^{[2
]}

Di Guida, Riccardo ^{[1
]}

Emiliani, Carla ^{[2
]}

Cross, Simon ^{[3
]}

机构：

[1] Univ Perugia, Dept Chem Biol & Biotechnol, Lab Chemoinformat & Mol Modelling, I-06123 Perugia, Italy

[2] Univ Perugia, Dept Chem Biol & Biotechnol, Lab Biochem & Mol Biol, I-06123 Perugia, Italy

[3] Mol Discovery, London HA55NE, England

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 92卷

关键词：

Phospholipidosis; Cationic amphiphilic drugs; Toxicophore; Modelling; HepG2; cells; Transmission electron microscopy; DRUG-INDUCED PHOSPHOLIPIDOSIS; INDUCED LYSOSOMAL STORAGE; CELL-BASED APPROACH; IN-VITRO; PREDICTING PHOSPHOLIPIDOSIS; HEPG2; CELLS; SULFATED GLYCOSAMINOGLYCANS; PHARMACOPHORE ELUCIDATION; COMPLEX-FORMATION; GENE-EXPRESSION;

D O I：

10.1016/j.ejmech.2014.12.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phospholipidosis (PLD) is an undesirable potential side-effect of drugs, and cationic amphiphilic drugs (CADs) represent the main class of PLD inducers. A CADs toxicophore has been recently proposed, although the CADs definition is far from being trivial. In this work we derive a three-dimensional CADs toxicophore (here named PLD-phore) using a molecular interaction field approach, and test its suitability to discriminate between PLD inducers and non-inducers in a virtual screening approach. Ten commercially available compounds predicted to be PLD inducers and non-inducers based on their similarity to the PLD-phore were experimentally tested for PLD induction using two cell-based in vitro assays (fluorescent lipid uptake, activity of secreted lysosomal beta-hexosaminidase). When a positive effect was observed, the PLD induction was also confirmed by transmission electron microscopy. Two exceptions to the general statement about CADs and PLD induction were detected and discussed, and for one compound the cell-based in-vitro assays lead to different outcomes. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：49 / 63

页数：15

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