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J Chem Inf Model. 2012 Jul 23;52(7):1798-805. doi: 10.1021/ci3001875. Epub 2012 Jul 5.

Structure based model for the prediction of phospholipidosis induction potential of small molecules.

Author information

1
National Institutes of Health (NIH) Chemical Genomics Center, NIH, Bethesda, Maryland 20892, United States. sunh7@mail.nih.gov

Abstract

Drug-induced phospholipidosis (PLD), characterized by an intracellular accumulation of phospholipids and formation of concentric lamellar bodies, has raised concerns in the drug discovery community, due to its potential adverse effects. To evaluate the PLD induction potential, 4,161 nonredundant drug-like molecules from the National Institutes of Health Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC), the Library of Pharmacologically Active Compounds (LOPAC), and the Tocris Biosciences collection were screened in a quantitative high-throughput screening (qHTS) format. The potential of drug-lipid complex formation can be linked directly to the structures of drug molecules, and many PLD inducing drugs were found to share common structural features. Support vector machine (SVM) models were constructed by using customized atom types or Molecular Operating Environment (MOE) 2D descriptors as structural descriptors. Either the compounds from LOPAC or randomly selected from the entire data set were used as the training set. The impact of training data with biased structural features and the impact of molecule descriptors emphasizing whole-molecule properties or detailed functional groups at the atom level on model performance were analyzed and discussed. Rebalancing strategies were applied to improve the predictive power of the SVM models. Using the undersampling method, the consensus model using one-third of the compounds randomly selected from the data set as the training set achieved high accuracy of 0.90 in predicting the remaining two-thirds of the compounds constituting the test set, as measured by the area under the receiver operator characteristic curve (AUC-ROC).

PMID:
22725677
PMCID:
PMC3484221
DOI:
10.1021/ci3001875
[Indexed for MEDLINE]
Free PMC Article

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