THE ROLE OF LIGAND FLEXIBILITY IN PREDICTING BIOLOGICAL-ACTIVITY - STRUCTURE-ACTIVITY-RELATIONSHIPS FOR ARYL-HYDROCARBON, ESTROGEN, AND ANDROGEN RECEPTOR-BINDING AFFINITY

Recent studies indicate that the potency and agonist or antagonist act ivity of steroid hormone ligands are dependent, in part, on ligand-rec eptor binding affinity as well as the conformation of the ligand-recep tor complex. The binding of ligands to hormone receptors is thought to involve interactions by which shapes of both the receptor and ligand are modified in the formation of the ligand-receptor complex. As a con sequence, it is essential to explore the significance of ligand flexib ility in the development of screening-level structure-activity relatio nships. In this review, examples are provided of techniques used to ge nerate and screen ligand conformers in the development of quantitative structure-activity relationships and active analogue search algorithm s. The biological endpoint modeled was binding affinity of natural lig ands and xenobiotics to the aryl hydrocarbon, estrogen, and androgen r eceptors. These approaches may be useful in future studies to evaluate relationships between ligand structure, receptor binding affinity, an d, ultimately, transactivational events associated with receptor inter actions with DNA response elements and associated proteins. An improve d understanding of ligand-receptor interactions in the context of well -defined effector systems will enhance the development of credible pre dictive models that can be used to screen large sets of chemicals for potential agonist or antagonistic activity.