A reaction mechanism-based prediction of mutagenicity: α-halo carbonyl compounds adduct with DNA by S2 reaction.

Most of the α-halo carbonyl (AHC) compounds tend to be predicted as mutagenic by structure-activity relationship based on structural category only, because they have an alkyl halide structure as a structural alert of mutagenicity. However, some AHC compounds are not mutagenic. We hypothesized that AHC reacts with DNA by S2 reaction, and the reactivity relates to mutagenicity. As an index of S2 reactivity, we focused on molecular orbitals (MOs), as the direction and position of two molecules in collision are important in the S2 reaction. The MOs suitable for S2 reaction (SN2MOs) were selected by chemical-visual inspection based on the shape of the MO. We used the level gap and the energy gap between SN2MO and the lowest unoccupied molecular orbital as the descriptors of S2 reactivity. As the results, S2 reactivity related to mutagenicity and we were able to predict mutagenicity of 20 AHC compounds with 95.0% concordance. It was suggested that S2 reaction is a reaction mechanism of AHC compounds and DNA in the mutagenic process. The method allows for discrimination among structurally similar compounds by combination with quantitative structure-activity relationships. The combination approach is expected to be useful for the mutagenic assessment of pharmaceutical impurities.