Steroid receptor structure and antihormone drug design

Abstract

A number of plant, insect, and vertebrate hormones modulate cell function by binding to protein carriers that are members of a superfamily of receptors capable of acting as transcription-activation signals [l-3]. Whereas the protein hormone receptors are generally localized in the membrane, those for steroids are almost exclusively soluble albeit their exact localization in the nonfunctional state remains debatable [l-3]. When a ligand comes in contact with the hormone binding domain (HBDt), a series of events lead to sequential, selective, and tissuespecific stimulation or suppression of genes that is limited in time and space. Recent identification of disease-specific receptor defects has imbued fresh life into the idea of a molecular solution to hormone based dysfunctions in humans [4,5]. The quest for agents capable of antagonizing hormone action assumes importance for a number of reasons. First and foremost, antihormones permit molecular dissection of the receptor such that the domain structure within the protein may be correlated with various functions. Second, products with antihormone action may be employed specifically to control hormone-regulated processes with wideranging implications in contraception, population control, hypertension, growth and development, and cancer, etc. This article will review the structure/function basis of receptor-mediated steroid hormone action as a prelude to the development of specific derivatives endowed with antagonist activity. The action of leading antihormone classes will be presented both with biological and clinical implications in an effort to stimulate debate on a future course of action.