Skin Sensitization Prediction
Using Quantum Chemical
Calculations: A Theoretical Model for the S<sub>N</sub>Ar Domain
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Abstract
It
is widely accepted that skin sensitization begins with the sensitizer
in question forming a covalent adduct with a protein electrophile
or nucleophile. We investigate the use of quantum chemical methods
in an attempt to rationalize the sensitization potential of chemicals
of the S<sub>N</sub>Ar reaction domain. We calculate the full reaction
profile for 23 chemicals with experimental sensitization data. For
all quantitative measurements, we find that there is a good correlation
between the reported pEC3 and the calculated barrier to formation
of the low energy product or intermediate (<i>r</i><sup>2</sup> = 0.64, <i>N</i> = 12) and a stronger one when
broken down by specific subtype (<i>r</i><sup>2</sup> >
0.9). Using a barrier cutoff of ∼10 kcal/mol allows us to categorize
100% (<i>N</i> = 12) of the sensitizers from the nonsensitizers
(<i>N</i> = 11), with just 1 nonsensitizer being mispredicted
as a weak sensitizer (9%). This model has an accuracy of ∼96%,
with a sensitivity of 100% and a specificity of ∼91%. We find
that the kinetic and thermodynamic information provided by the complete
profile can help in the rationalization process, giving additional
insight into a chemical’s potential for skin sensitization