Classical and three-dimensional quantitative structure-activity analyses of steroid hormones: Structure-receptor binding patterns of anti-hormonal drug candidates

Abstract Previous QSAR (quantitative structure-activity relationships) examples of steroid hormones were briefly surveyed. The absorption and distribution processes and pharmacological activities in which transport factors are critical are governed mainly by molecular hydrophobicity. When the expression of the overall biological activity is controlled by the binding-affinity with the receptor sites as the rate-limiting process, the QSAR pattern is more complicated, because stereoelectronic and hydrogen-bonding effects of substituents or substructures of the molecule are usually involved in the structure-affinity relationships. The binding affinities of a number of androstan-17β-ols and estratrien-17β-ols for androgen and estrogen receptor preparations were experimentally measured and their structure-affinity relationships were analyzed using classical and three-dimensional (CoMFA) QSAR procedures. The regiospecific stereoelectronic properties of the molecule were found to significantly regulate the affinity in each pair of combinations between ligand and receptor species. The hydrophobicity was of minor importance. The classical and CoMFA procedures were complementary to each other, illustrating the “components” involved in physicochemical and structural requirements for the binding affinity. The structural features of epitiostanol, an, antiestrogen, which is an androstanol derivative that has been marketed as an anti-breast cancer agent, agreed very well with the QSAR patterns from the two procedures.