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Lazy structure-activity relationships (lazar) for the prediction of rodent carcinogenicity and Salmonella mutagenicity

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Abstract

lazar is a new tool for the prediction of toxic properties of chemical structures. It derives predictions for query structures from a database with experimentally determined toxicity data. lazar generates predictions by searching the database for compounds that are similar with respect to a given toxic activity and calculating the prediction from their activities. Apart form the prediction, lazar provides the rationales (structural features and similar compounds) for the prediction and a reliable condence index that indicates, if a query structure falls within the applicability domain of the training database.

Leave-one-out (LOO) crossvalidation experiments were carried out for 10 carcinogenicity endpoints ({female|male} {hamster|mouse|rat} carcinogenicity and aggregate endpoints {hamster|mouse|rat} carcinogenicity and rodent carcinogenicity) and Salmonella mutagenicity from the Carcinogenic Potency Database (CPDB). An external validation of Salmonella mutagenicity predictions was performed with a dataset of 3895 structures. Leave-one-out and external validation experiments indicate that Salmonella mutagenicity can be predicted with 85% accuracy for compounds within the applicability domain of the CPDB. The LOO accuracy of lazar predictions of rodent carcinogenicity is 86%, the accuracies for other carcinogenicity endpoints vary between 78 and 95% for structures within the applicability domain.

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Abbreviations

CCRIS:

chemical carcinogenesis research information system

CPDB:

carcinogenic potency database

DSSTox:

distributed structure-searchable toxicity project

lazar:

lazy structure-activity relationships

LOO:

leave-one-out crossvalidation

k-nn:

k-nearest-neighbours

(Q)SAR:

(quantitative) structure-activity relationships

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  1. In Silico Toxicology, Talstraße 20, D-79102, Freiburg, Germany

    Christoph Helma

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  1. Christoph Helma
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Correspondence to Christoph Helma.

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Helma, C. Lazy structure-activity relationships (lazar) for the prediction of rodent carcinogenicity and Salmonella mutagenicity. Mol Divers 10, 147–158 (2006). https://doi.org/10.1007/s11030-005-9001-5

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