Molecular modeling of steroidal estrogens: novel conformations and their role in biological activity

Since the structure and conformation of many estrogenic ligands cannot be described with X-ray crystallographic studies, molecular modeling techniques must be used to generate their 3-dimensional structures. The potential of three molecular modeling methods to simulate the X-ray crystallographic geometry of estradiol-17 beta and various analogs (estratrien-1,17 beta-diol, estratrien-2,17 beta-diol, estratrien-3,11 alpha,17 beta-triol, estratrien-3,11 beta,17 beta-triol, 9 beta-estratrien-3,17 beta-diol-11-one) have been compared. MMP2 molecular mechanics as well as the MOPAC semi-empirical molecular orbital methods, AM1 and PM3, were examined in these studies of estrogens with unique ring distortions. Whereas all three methods were able to simulate reasonable estrogen structures, the MMP2 method was found to reproduce the X-ray geometry of estrogens better than the MOPAC methods. The contribution of crystal packing distortions on the X-ray structures in these comparisons is discussed. Additionally, a molecular modeling dynamics method for the systematic conformational searching of steroidal estrogens is presented. For each estrogen examined, conformational searching produced at least one unique steroid conformation in addition to the X-ray crystallographic geometry. The MMP2 potential energy of predicted conformations and transition barriers of these estrogens has been shown to be less than the free energy of receptor binding. Thus, it is conceivable that estrogen ligands which can exist in a number of conformations may be converted to a preferred geometry by binding within the specific site of receptor. Furthermore, it is suggested that conformational flexibility of estrogens may be an important property of specific ligands for the estrogen receptor.