2001 Volume 1 Issue 2 Pages 60-72
The structures of dioxins were optimized by the ab initio molecular orbital method at the HF/6-31G* level with the Gaussian 98 program package, and then electrostatic potentials were mapped out to explore the pharmacophore image of the receptor complementary to that. The maps were additive on the constitutional atoms, showing similarly the negative values around the oxygen and chlorine atoms and the positive values around the carbon and hydrogen atoms; and with the similarity of the molecular shapes, the applicability of the Comparative Molecular Field Analysis (CoMFA) was anticipated. Total 18 compounds, to which the toxic equivalency factors (WHO-TEF) are given, were used for CoMFA. These compounds consist of three congeners: polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar poly-chlorinated biphenyls (Coplanar PCBs). CoMFA was executed by using the receptor binding avidities (EC50) as the activity. The receptor was rat hepatic cytosol aryl hydrocarbon receptor (AhR). The structures were superimposed by fitting pairs of atoms so as to minimize RMS of the distances. As the template molecule 1, 2, 3, 7, 8-PeCDD was selected. PCDFs were superimposed to PCDDs in planar position, but twisted PCBs went through from one side of PCDD to the other side. Electrostatic potential derived charges of CHelpG by ab initio HF/6-31G* calculations were given to the structures. Partial least squares gave a cross-validated correlation coefficient q² = 0.955 at the number of components 3. From the correlation, extrapolation to the higher value of bromine derivatives as 2, 3, 7, 8-TBrDD and interpolation to the lower value as 1, 3, 7, 8-TCDD were done.
