94-104
TOXICOPHORES AND QUANTITATIVE STRUCTURE -TOXICITY RELATIONSHIPS FOR SOME ENVIRONMENTAL POLLUTANTS
Authors: N. N. Gorinchoy, I. Ya. Ogurtsov, A. Tihonovschi, I. Balan, I. B. Bersuker, A. Marenich and J.Boggs
Number of views: 430
The electron-conformational (EC) method is employed to reveal the toxicophore and to predict
aquatic toxicity quantitatively using as a training set a series of 51 compounds that have aquatic toxicity to fi sh.
By performing conformational analysis (optimization of geometries of the low-energy conformers by the PM3
method) and electronic structure calculations (by ab initio method corrected within the SM54/PM3 solvatation
model), the Electron-Conformational Matrix of Congruity (ECMC) was constructed for each conformation of these
compounds. The toxicophore defi ned as the EC sub-matrix of activity (ECSA), a sub-matrix with matrix elements
common to all the active compounds under consideration within minimal tolerances, is determined by an iterative
procedure of comparison of their ECMC’s, gradually minimizing the tolerances. Starting with only the four most
toxic compounds, their ECSA (toxicophore) was found to consists of a 4x4 matrix (four sites with certain electronic
and topologic characteristics) which was shown to be present in 17 most active compounds. A structure-toxicity
correlation between three toxicophore parameters and the activities of these 17 compounds with R2=0.94 was found.
It is shown that the same toxicophore with larger tolerances satisfi es the compounds with les activity, thus explicitly
demonstrating how the activity is controlled by the tolerances quantitatively and which atoms (sites) are most fl exible
in this respect. This allows for getting slightly different toxicophores for different levels of activity. For some active
compounds that have no toxicophore a bimolecular mechanism of activity is suggested. Distinguished from other
QSAR methods, no arbitrary descriptors and no statistics are involved in this EC structure-activity investigation.