title: In silico assay for assessing phospholipidosis potential of small druglike molecules: training, validation, and refinement using several data sets.
abstract: Phospholipidosis (PLD) is a lysosomal storage disorder induced by compounds, notably cationic amphiphilic drugs, which although reversible interferes with cellular phospholipids.The in silico method described utilizes the amphiphilic moment ΔΔG(AM) (kJ/mol) together with basic pK(a) values to assign PLD inducing potential to a compound. The new model was accurate and sensitive (85% and 82%, respectively) when compared to other data sets. Therefore, the parallel in vitro assay for PLD was discontinued. The data reinforce our view that the amphiphilic moment is far more informative for determining a compound's potential to induce PLD than the combined use of basic pK(a) and ClogP values.
authors: Clinical Safety/Licensing and Early Development, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland. Holger.fischer@roche.com
authors: Holger
authors: H
authors: Fischer
authors: Elke-Astrid
authors: EA
authors: Atzpodien
authors: Miklos
authors: M
authors: Csato
authors: Lucette
authors: L
authors: Doessegger
authors: Barbara
authors: B
authors: Lenz
authors: Georg
authors: G
authors: Schmitt
authors: Thomas
authors: T
authors: Singer
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003198:Computer Simulation; D003315:Cornea / Q000166:cytology; D064420:Drug-Related Side Effects and Adverse Reactions; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D008064:Lipidoses / Q000139:chemically induced / Q000378:metabolism*; D016464:Lysosomal Storage Diseases / Q000139:chemically induced / Q000378:metabolism*; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations; D010743:Phospholipids