3-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 anal ysis (CoMFA), a three-dimensional quantitative structure-activity rela tionship paradigm, to explore the physicochemical requirements for bin ding to the Ah (dioxin) receptor. Recent developments by Gillner et al . [(1993) Mol. Pharmacol. 44, 336-345] prompted us to review and revis e our previous CoMFA/QSAR model [Waller, C. L., and McKinney, J. D. (1 992) J. Med. Chem. 36, 3660-3666] to include a structurally-diverse tr aining set of Ah receptor ligands ranging in size from naphthalene to indolo[3,2-b]carbazole nuclei. An exhaustive validation process utiliz ing external test sets and hierarchical cluster analysis routines was employed during model construction and is discussed herein. The limita tions of the approach presented herein are discussed with respect to p redictive ability of the CoMFA/QSAR models, which is demonstrated to b e dependent on a balance between structural diversity and redundancy i n the molecules comprising the training set. The results of our modifi ed CoMFA/QSAR model are consistent with and unify all previously estab lished structure-activity relationships established for less structura lly-diverse training sets of Ah receptor ligands. As a result of the m ore complete nature of the series of molecules under examination in th e 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 th e Ah receptor. The implications of the CoMFA/QSAR model presented here in are explored with respect to quantitative hazard identification of potential toxicants.