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 activity of steroid hormone ligands are dependent, in part, on ligand–receptor binding affinity as well as the conformation of the ligand–receptor 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 consequence, it is essential to explore the significance of ligand flexibility in the development of screening-level structure–activity relationships. In this review, examples are provided of techniques used to generate and screen ligand conformers in the development of quantitative structure–activity relationships and active analogue search algorithms. The biological endpoint modeled was binding affinity of natural ligands and xenobiotics to the aryl hydrocarbon, estrogen, and androgen receptors. These approaches may be useful in future studies to evaluate relationships between ligand structure, receptor binding affinity, and, ultimately, transactivational events associated with receptor interactions with DNA response elements and associated proteins. An improved understanding of ligand–receptor interactions in the context of well-defined effector systems will enhance the development of credible predictive models that can be used to screen large sets of chemicals for potential agonist or antagonistic activity. Keywords—Structure–activity relationships Receptor binding affinity Aryl hydrocarbon receptor Androgen receptor Estrogen receptor