Mutagenicity, prediction

Kazius, J., McGuire, R., Bursi, R. Derivation and validation of toxicophores for mutagenicity prediction. J. Med. 

Zeiger E. 1987. Carcinogenicity of mutagens Predictive capability of the Salmonella mutagenesis assay for rodent carcinogenicity. Cancer Res 47(5) 1287-1296. 

Table 1 DfW mutagenicity predictions (version 7.0) and Ames results for 1441 Aventis proprietary structures.

In our contribution we have focused the discussion on descriptors. The understanding of descriptors is essential for transparency of models and can also lead to mechanistic interpretation of models. Several questions are associated with descriptors. First of all, nowadays thousand of descriptors are defined and can be easily calculated with available software and the first question is how to the select the most relevant descriptors. The topological descriptors are sometimes promising, but there is no clear physicochemical interpretation for them. 3D molecular structure is a problematic quantity as it depends on the media where the molecule is, or on the method of determination. Quantum chemical descriptors, which have a clear physicochemical interpretation, are difficult to calculated. In the cases studies we have addressed some of those questions. We have discussed the sensitivity of the models, and particularly predictions, to descriptors used. According to the critical review of Snyder and Smith [87] on QSAR models for mutagenicity prediction a lot of work still remains to be done. 

Figure 10.25 Twenty-nine specific toxicophores for mutagenicity as identified by Kazius el al. (Kazius, J-, et al. Derivation and validation of toxicophores for mutagenicity prediction. J. Med. Chem. 2005, 48, 312-320.) (A) Specific aromatic nitro, (B) specific aromatic amine, (C) aromatic nitroso, (D) alkyl nitrite, (E) nitrosamine, (F) epoxide, (G) aziridine, (H) azide, (I) diazo, (J) triazene, (K) aromatic azo, (L) unsubstituted heteroatom-bonded heteroatom, (M) aryl hydroxylamine, (N) alkyl halide, (O) acyl halide, (P) N- or 5-mustard, (Q) polycyclic aromatics, (R) bay-region, (S) K-region, (T) sulphonate-bonded C, (U) unsaturated aldehyde, (V) alkyl A-nitro, (W) diazonium, (X) p-propiolactone, (Y) unsubstituted a,p unsaturated alkoxy, (Z) l-aryl-2-monoalkyl hydrazine, (AA) aromatic methylamine, (AB) aryl hydroxylamine ester, and (AC) polycyclic planar system.

Hillebrecht, A., Muster, W., Brigo, A., Kansy, M., Weiser, T., Singer, T. (2011). Comparative evaluation of in silico systems for ames test mutagenicity prediction scope and limitations. Chemical Research in Toxicology, 24, 843-854. 

C. Meinert, E. Schymanski, E. Kiister, R. Kiihne, G. Schiiiirmann, and W. Brack. Application of preparative capillary gas chromatography (pcGC), automated structure generation and mutagenicity prediction to improve effect-directed analysis of genotoxicants in a contaminated groundwater. Environ. Sci. Pollut. Res., 17(4) 885-897, 2010. 

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