J Chem Inf Model - Modeling phospholipidosis induction: reliability and warnings.

Tópicos

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Resumo

Drug-induced phospholipidosis (PLD) is characterized by accumulation of phospholipids, the inducing drugs and lamellar inclusion bodies in the lysosomes of affected tissues. These side effects must be considered as early as possible during drug discovery, and, in fact, numerous in silico models designed to predict PLD have been published. However, the quality of any in silico model cannot be better than the quality of the experimental data set used to build it. The present paper reports an overview of the difficulties and errors encountered in the generation of databases used for the published PLD models. A new database of 466 compounds was constructed from seven literature sources, containing only publicly available compounds. A comparison of the PLD assignations in selected databases proved useful in revealing some inconsistencies and raised doubts about the previously assigned PLD+ and PLD- classifications for some chemicals. Finally, a Partial Least Squares Discriminant Analysis (PLS-DA) approach was also applied, revealing further anomalies and clearly showing that metabolism as well as data quality must be taken into account when generating accurate methods for predicting the likelihood that a compound will induce PLD. A new curated database of 331 compounds is proposed.

Resumo Limpo

druginduc phospholipidosi pld character accumul phospholipid induc drug lamellar inclus bodi lysosom affect tissu side effect must consid earli possibl drug discoveri fact numer silico model design predict pld publish howev qualiti silico model better qualiti experiment data set use build present paper report overview difficulti error encount generat databas use publish pld model new databas compound construct seven literatur sourc contain public avail compound comparison pld assign select databas prove use reveal inconsist rais doubt previous assign pld pld classif chemic final partial least squar discrimin analysi plsda approach also appli reveal anomali clear show metabol well data qualiti must taken account generat accur method predict likelihood compound will induc pld new curat databas compound propos

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