Orbital Calculations and QSARs in Toxicity

The Pullmans were the first to use electronic structure calculations in several studies on the carcinogenicity of polycyclic aromatic hydrocarbons and hetero analogs in the late 1940s and early 1950s. Much of the early work on 

Electrostatic isopotential (EIP) minima186 often identify sites and ease of metabolism by epoxide hydrase, an enzyme responsible for the conversion of epoxides to diols by the addition of water. Molecular electrostatic potential energy calculations also are probably the best means of identifying positions of epoxidation and, possibly, metabolism in general. In the case of aflatoxin B for example, EIP maxima and minima calculated by the CNDO/2 method all lie close to the known sites of metabolism and, in particular, the formation of the carcinogenic 2,3-epoxide is readily predicted.189 

An electronic parameter that often correlates with metabolic rates is the electrophilic (or nucleophilic) superdelocalizability. This quantity is a reactivity index formulated by Fukui and colleagues as an orbital-weighted electron density.145 The total electrophilic superdelocalizability, 2SE, summed over all atoms in a molecule, exhibits a parallelism with the hydrophobic parameter, log P, in several series of compounds such as PAHs and aliphatic amines, where it is probably approximating molecular volume. 

As mentioned earlier, the logarithm of the octanol/water partition coefficient is an extremely important quantity in toxicological evaluations. Hansch 

Arene oxides Marsh and Jerina 1978 Transition state energies 223 

---