Merck
  • Home
  • Search Results
  • Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.

Development of a phospholipidosis database and predictive quantitative structure-activity relationship (QSAR) models.

Toxicology mechanisms and methods (2008-01-01)
Naomi L Kruhlak, Sydney S Choi, Joseph F Contrera, James L Weaver, James M Willard, Kenneth L Hastings, Lawrence F Sancilio
ABSTRACT

ABSTRACT Drug-induced phospholipidosis (PL) is a condition characterized by the accumulation of phospholipids and drug in lysosomes, and is found in a variety of tissue types. PL is frequently manifested in preclinical studies and may delay or prevent the development of pharmaceuticals. This report describes the construction of a database of PL findings in a variety of animal species and its use as a training data set for computational toxicology software. PL data and chemical structures were compiled from the published literature, existing pharmaceutical databases, and Food and Drug Administration (FDA) internal reports yielding a total of 583 compounds suitable for modeling. The database contained 190 (33%) positive drugs and 393 (77%) negative drugs, of which 39 were electron microscopy-confirmed negative compounds and 354 were classified as negatives due to the absence of positive reported data. Of the 190 positive findings, 76 were electron microscopy confirmed and 114 were considered positive based on other evidence. Quantitative structure-activity relationship (QSAR) models were constructed using two commercially available software programs, MC4PC and MDL-QSAR, and internal cross-validation (10 x 10%) experiments were performed to assess their predictive performance. Performance parameters for the MC4PC model were specificity 92%, sensitivity 50%, concordance 78%, positive predictivity 76%, and negative predictivity 78%. For MDL-QSAR, predictive performance was similar: specificity 80%, sensitivity 76%, concordance 79%, positive predictivity 65%, and negative predictivity 87%. By combining the output of the two QSAR programs, the overall predictive performance was vastly improved and sensitivity could be optimized to 81% without significant loss of specificity (79%). Many of the structural alerts and significant molecular descriptors obtained from the QSAR software were found to be associated with parts of active molecules known for their cationic amphiphilic drug (CAD) properties supporting the hypothesis that the endpoint of PL is statistically correlated with chemical structure. QSAR models can be useful tools for screening drug candidate molecules for potential PL.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Glycine 1 M solution
Supelco
Ofloxacin, VETRANAL®, analytical standard
Sigma-Aldrich
Benzyl alcohol, ReagentPlus®, ≥99%
Sigma-Aldrich
Benzyl alcohol, puriss. p.a., ACS reagent, ≥99.0% (GC)
Sigma-Aldrich
Benzyl alcohol, ACS reagent, ≥99.0%
Sigma-Aldrich
Glycerol, puriss. p.a., ACS reagent, anhydrous, dist., ≥99.5% (GC)
Sigma-Aldrich
Glycerol, ReagentPlus®, ≥99.0% (GC)
Sigma-Aldrich
Glycerol, ACS reagent, ≥99.5%
Sigma-Aldrich
Glycerol, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, E422, anhydrous, 99.0-101.0% (alkalimetric)
Sigma-Aldrich
Benzyl alcohol, puriss., meets analytical specification of Ph. Eur., BP, NF, 99-100.5% (GC)
Sigma-Aldrich
1α,25-Dihydroxyvitamin D2 solution, 100 μg/mL in ethanol, 95% (CP)
Sigma-Aldrich
Acetaminophen, analytical standard
Sigma-Aldrich
DL-Lactic acid, 85 % (w/w), syrup
Sigma-Aldrich
DL-Leucine, ≥99% (HPLC)
Sigma-Aldrich
Acetaminophen, meets USP testing specifications, 98.0-102.0%, powder
Sigma-Aldrich
Acetaminophen, BioXtra, ≥99.0%
Sigma-Aldrich
(±)-Thalidomide, ≥98%, powder
Sigma-Aldrich
Cytosine β-D-arabinofuranoside, crystalline, ≥90% (HPLC)
Sigma-Aldrich
Tamoxifen, ≥99%
Sigma-Aldrich
5-Fluorocytosine, nucleoside analog
Sigma-Aldrich
Glycerol, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for electrophoresis, ≥99% (GC)
Sigma-Aldrich
Oxolinic acid, quinolone antibiotic
Supelco
Isoniazid, analytical standard, ≥99% (TLC)
Sigma-Aldrich
Nitrendipine, >95%, powder
Sigma-Aldrich
Glycerol, for molecular biology, ≥99.0%
Sigma-Aldrich
Glycerol, ≥99.5%
Sigma-Aldrich
N-(2-Mercaptopropionyl)glycine
Sigma-Aldrich
Glycerol, BioXtra, ≥99% (GC)
Supelco
Sulfamethoxazole, analytical standard
Sigma-Aldrich
(±)-Thiopental