Three-dimensional quantitative structure-activity relationships of dioxins and dioxin-like compounds: model validation and Ah receptor characterization.

In the present study we have utilized comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship paradigm, to explore the physico-chemical requirements for binding to the Ah (dioxin) receptor. Recent developments by Gillner et al. [(1993) Mol. Pharmacol. 44, 336-345] prompted us to review and revise our previous CoMFA/QSAR model [Waller, C. L., and McKinney, J. D. (1992) J. Med. Chem. 36, 3660-3666] to include a structurally-diverse training set of Ah receptor ligands ranging in size from naphthalene to indolo[3,2-b]carbazole nuclei. An exhaustive validation process utilizing external test sets and hierarchical cluster analysis routines was employed during model construction and is discussed herein. The limitations of the approach presented herein are discussed with respect to predictive ability of the CoMFA/QSAR models, which is demonstrated to be dependent on a balance between structural diversity and redundancy in the molecules comprising the training set. The results of our modified CoMFA/QSAR model are consistent with and unify all previously established structure-activity relationships established for less structurally-diverse training sets of Ah receptor ligands. As a result of the more complete nature of the series of molecules under examination in the present study, the CoMFA/QSAR steric and electrostatic field contour plots as well as the essential and excluded volume plots provide for a more detailed characterization of the molecular binding domain of the Ah receptor. The implications of the CoMFA/QSAR model presented herein are explored with respect to quantitative hazard identification of potential toxicants.