title: Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach.
abstract: 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 β-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.
authors.affiliation: Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, I-06123 Perugia, Italy. Electronic address: laura.goracci@unipg.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, I-06123 Perugia, Italy. Electronic address: sandra.buratta@unipg.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Buratta
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, I-06123 Perugia, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Urbanelli
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, I-06123 Perugia, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Ferrara
authors.affiliation: Laboratory for Chemoinformatics and Molecular Modelling, Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, I-06123 Perugia, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Di Guida
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, I-06123 Perugia, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Emiliani
authors.affiliation: Molecular Discovery, 215 Marsh Road, Pinner, HA55NE London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Cross
mesh_terms: D002412:Cations / Q000009:adverse effects; D006801:Humans; D010743:Phospholipids / Q000096:biosynthesis* / Q000097:blood*; D018570:Risk Assessment; D013501:Surface-Active Agents / Q000009:adverse effects*
chemical_list: D002412:Cations; D010743:Phospholipids; D013501:Surface-Active Agents
keywords: Cationic amphiphilic drugs; HepG2 cells; Modelling; Phospholipidosis; Toxicophore; Transmission electron microscopy