title: Comparative evaluation of in silico systems for ames test mutagenicity prediction: scope and limitations.
abstract: The predictive power of four commonly used in silico tools for mutagenicity prediction (DEREK, Toxtree, MC4PC, and Leadscope MA) was evaluated in a comparative manner using a large, high-quality data set, comprising both public and proprietary data (F. Hoffmann-La Roche) from 9,681 compounds tested in the Ames assay. Satisfactory performance statistics were observed on public data (accuracy, 66.4-75.4%; sensitivity, 65.2-85.2%; specificity, 53.1-82.9%), whereas a significant deterioration of sensitivity was observed in the Roche data (accuracy, 73.1-85.5%; sensitivity, 17.4-43.4%; specificity, 77.5-93.9%). As a general tendency, expert systems showed higher sensitivity and lower specificity when compared to QSAR-based tools, which displayed the opposite behavior. Possible reasons for the performance differences between the public and Roche data, relating to the experimentally inactive to active compound ratio and the different coverage of chemical space, are thoroughly discussed. Examples of peculiar chemical classes enriched in false negative or false positive predictions are given, and the results of the combined use of the prediction systems are described.
authors.affiliation: F. Hoffmann-La Roche Ltd., Non-Clinical Safety, Basel CH-4070, Switzerland. alexander.hillebrecht@roche.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillebrecht
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Muster
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brigo
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
authors.forename: Thomas
authors.initials: T
authors.lastname: Weiser
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D012984:Software
chemical_list: D009153:Mutagens