Structure-activity relationship studies of carcinogenic activity of polycyclic aromatic hydrocarbons using calculated molecular descriptors with principal component analysis and neural network methods.

Recently a new methodology based on local density of state (LDOS) calculations using topological and semiempirical methods was proposed to identify the carcinogenic activity of polycyclic aromatic hydrocarbons (PAHs). In this work we perform a comparative study of this methodology with principal component analysis (PCA) and neural networks (NN). The PCA and NN results show that LDOS quantum chemical descriptors are relevant descriptors to identify the carcinogenic activity of methylated and non-methylated PAHs. Also, we show that the combination of these distinct methodologies can be an efficient and powerful tool in the structure-activity studies of PAHs compounds. We have studied 81 methylated and non-methylated PAHs, and our study shows that with the use of these methods it is possible to correctly predict the carcinogenic activity of PAHs with accuracy higher than 80%.

Molecular mechanics explanation for the stereochemical and shape selectivity of B-DNA for "bay-region" carcinogens.

The equilibrium structures of 20 intercalated physical complexes of "bay-region" triol carbocations of polycyclic aromatic hydrocarbons (PAHs) with B-DNA are obtained by AMBER molecular modeling. The complexes with highly potent carcinogens are found (i) to undergo only minor conformational changes upon complexation, (ii) to be stabilized by hydrogen bonds between two hydroxyl groups of the triol carbocations and N3 atoms of the adjacent guanine residues, and (iii) to be "preorganized" for covalent bonding. A new explanation for the absolute stereochemical and shape dependence of carcinogenesis by PAHs is presented. The biologically active conformers of both carcinogenic stereoisomers (anti and syn) of triol carbocations are characterized by a quasi-diaxial orientation of the neighboring hydroxyl groups and fulfill the spatial requirements for hydrogen bonding to the adjacent guanine residues of B-DNA. The striking dependence of potency on the shape of the PAHs is largely caused by repulsion from the C2'-methylene groups of the deoxyribose residues of DNA. This interaction may shift the intercalated triol carbocation, thereby enhancing or reducing the preorganization for covalent bonding. The molecular modeling study is augmented by benchmark ab initio calculations on the bay-region triol carbocation of phenanthrene.