title: The mechanism of action of steroid antagonists: insights from crystallographic studies.
abstract: Examination of the structures of compounds having high affinity for estrogen, progestin, mineralocorticoid and glucocorticoid receptors strongly suggests that receptor binding is primarily the result of a tight association between the receptor and the steroidal A-ring. High affinity binding to the estrogen receptor appears to be dependent upon the presence of a phenolic ring in the substrate. An inverted 1 beta, 2 alpha conformation of the 4-ene-3-one A-ring appears to be most conductive to high affinity binding to the progesterone receptor. Binding to the mineralocorticoid receptor appears to be correlated to a complementary fit between amino acids of the receptor site and a flat 4-en-3-one A-ring similar to that imposed upon aldosterone by the 11,18-epoxide formation. The glucocorticoid receptor appears to prefer a 4-en-3-one A-ring that is bowed toward the alpha-face as is the case in structures having a 9 alpha-fluoro substituent or additional unsaturation at C(1)-C(2). The binding of androgens to their receptor differs in appearing to have an essential dependence upon functional groups at the A- and D-ring end of the steroid. With the exception of the androgens, the data suggest that specific interactions between the steroid B-, C- and D-rings and the receptor play at best a minor role in receptor binding but are the most important factor in determining agonist versus antagonist behavior subsequent to binding. Antagonists that compete for a steroid receptor site may be expected to have the A-ring composition and conformation necessary for receptor binding but lack the 11 beta-OH and the D-ring conformational features and functional groups that induce or stabilize subsequent receptor functions. Antagonists might also be compounds with A-ring conformations appropriate for binding but other structural features that interfere with subsequent receptor functions essential to activity.
authors.affiliation: Medical Foundation of Buffalo, Inc., NY 14203.
authors.forename: W L
authors.initials: WL
authors.lastname: Duax
authors.forename: J F
authors.initials: JF
authors.lastname: Griffin
authors.forename: C M
authors.initials: CM
authors.lastname: Weeks
authors.forename: Z
authors.initials: Z
authors.lastname: Wawrzak
mesh_terms: D000726:Androgen Antagonists; D000728:Androgens; D000818:Animals; D003198:Computer Simulation; D003461:Crystallography; D004965:Estrogen Antagonists; D004967:Estrogens; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D006801:Humans; D008901:Mineralocorticoids / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D011372:Progestins / Q000037:antagonists & inhibitors; D011987:Receptors, Steroid / Q000187:drug effects*; D013256:Steroids / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D004965:Estrogen Antagonists; D004967:Estrogens; D005938:Glucocorticoids; D008901:Mineralocorticoids; D011372:Progestins; D011987:Receptors, Steroid; D013256:Steroids