Structure and conformation of glucocorticoids.

The approaches currently available for determining the structure and conformation of glucocorticoids are reviewed. We discuss the optimization of steroid geometry based on the relative molecular energy calculated by a Westheimer equation. This method permits an extensive description of steroid molecules in a state free of external constraints and which can be assumed to correspond to the minimum internal energy. The structures, conformations, surface areas, and volumes of fifteen steroid molecules that interact with the glucocorticoid receptor have been studied. The basic structure of the A ring is a 1 alpha,2 beta-half-chair, whatever the substitutions. Rings B and C are semi-rigid chairs virtually uninfluenced by substituent groups. In contrast, the shape of the D ring depends on the nature and environment of the substituents. As to the fundamental conformation of the side chain, the steroids fall into two categories, depending on the pressure of a 17-hydroxyl group. For a given molecule, the energy changes associated with conformations of the side chain other than that corresponding to the minimum energy have also been explored. The hypothesis is formulated that receptor binding requires a particular conformation of the side chain. Finally, the overall shape of the molecule can be influenced by the summation of minor but numerous changes brought about by various substitutions, such as 11 beta-hydroxyl, which increases the convexity of the molecule. These investigations should help in elucidating structure-activity relationships for glucocorticoids. They may improve our knowledge of the interaction between these hormones and their receptor and of the molecular mechanism of glucocorticoid action.