Structure-activity relationships for glucocorticoids—IV. Effects of substituents on the overall shape of steroids which bind to the glucocorticoid receptor

Abstract

The lowest molecular energy structure of 24 steroids which bind to the glucocorticoid receptor has been determined by geometry optimisation. In this paper we analyze selected structural parameters which describe the overall shape of the steroid molecule. The structural influence of 10 different substitutions has been quantitatively assessed by Free and Wilson analysis. The substituents have little if any effect on the distribution of carbon atoms relative to the various mean planes they participate in. Exceptions are the 1-ene unsaturation which flattens the A-ring mean plane and the 6-ene unsaturation which puckers the plane of the C18, C19 methyls. The convexity of the steroid skeleton is increased by the 1-ene and the 11β-hydroxy substitutions while it is decreased by the presence of a 17-hydroxyl group. The twist of the molecule along its long axis is abolished by a 1-ene and reversed by a 7-ene unsaturation. As to the dihedral angle of the side-chain with other planes of reference it is variously perturbed significantly by 7 different substitutions. Some of these effects are illustrated by scaled projected pictures of the steroid molecules. Finally, we have computed molecular surface area and volume parameters and determined to what extent they are modified by the substitutions in our series of steroids. Together with data presented in the other papers of this series, the studies reported should help investigating the relationships between the structure of steroids and their glucocorticoid properties.