Assessment of Methods To Define the Applicability Domain of Structural Alert Models

Abstract

It is important that in silico models for use in chemical safety legislation, such as REACH, are compliant with the OECD Principles for the Validation of (Q)SARs. Structural alert models can be useful under these circumstances but lack an adequately defined applicability domain. This paper examines several methods of domain definition for structural alert models with the aim of assessing which were the most useful. Specifically, these methods were the use of fragments, chemical descriptor ranges, structural similarity, and specific applicability domain definition software. Structural alerts for mutagenicity in Derek for Windows (DfW) were used as examples, and Ames test data were used to define and test the domain of chemical space where the alerts produce reliable results. The usefulness of each domain was assessed on the criterion that confidence in the correctness of predictions should be greater inside the domain than outside it. By using a combination of structural similarity and chemical fragments a domain was produced where the majority of correct positive predictions for mutagenicity were within the domain and a large proportion of the incorrect positive predictions outside it. However this was not found for the negative predictions; there was little difference between the percentage of true and false predictions for inactivity which were found as either within or outside the applicability domain. A hypothesis for the occurrence of this difference between positive and negative predictions is that differences in structure between training and test compounds are more likely to remove the toxic potential of a compound containing a structural alert than to add an unknown mechanism of action (structural alert) to a molecule which does not already contain an alert. This could be especially true for well studied end points such as the Ames assay where the majority of mechanisms of action are likely to be known.

Mutagenic and carcinogenic structural alerts and their mechanisms of action

“…Benigni and Bossa (24) summarised structural alerts as follows: "The Structural Alerts are molecular substructures or reactive groups that are related to the carcinogenic and mutagenic properties of the chemicals, and represent a sort of 'codification' of a long series of studies aimed at highlighting the mechanisms of action of the mutagenic and carcinogenic chemicals". Structural alerts are very helpful not only in the classification of potential carcinogens, but are also important in understanding the mechanisms of genotoxicity (24)(25)(26)(27)(28). …”

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

“…In other words, if a compound does not contain a structural alert, how much confidence is there that it is not a DNA-reactive mutagen? This topic has stimulated much debate (Ellison et al 2011). The reality is that it is widely acknowledged that predictions of DNA-reactive mutagenicity from structural alerts are likely to be more acceptable (from a precautionary perspective) than negative predictions.…”

Ensuring confidence in predictions: A scheme to assess the scientific validity of in silico models

“…It must be remembered that the applicability domain is a complicated issue with many different approaches one can take in its definition. Even for the aforementioned structural alerts models, defining the applicability domain can be a complex task [32]. Within eTOX, the new release of eTOXsys is now able to accept applicability domain information, aiding in its characterisation.…”