Steroid hormone structure, receptor binding and activity: empirical drug design

摘要

Steroid hormones play a vital role in a wide variety of essential physiological processes including cell growth, sexual development, maintenance of salt balance and sugar metabolism. Because of the key role that steroids play in human health and disease therapy, an understanding of the molecular details of steroid hormone action is essential. Small changes in the number and position of functional groups on the steroid nucleus result in large differences in activity. Many of these processes are known to be dependent upon initial binding of the steroid to a specific cytosolic protein receptor and the subsequent interaction of the steroid-receptor complex with chromain. An examination of the three-dimensional shapes of the hormones, antihormones, chemicals and the drugs that compete for a common binding site on a specific receptor binding protein or metabolizing enzyme can provide information on structural features that influence hormonal response. Crystallographic data on over 1000 steroids provide information concerning preferred conformations, relative stabilities and substituent influence on the interactive potential of steroid hormones and analogs. Systematic conformational analysis of subsets of these data having common structural features suggests that steroids crystallize in global minimum energy conformations or local minimum energy conformations that are less than two kcal mol~(-1) above the global minimum.