Stereochemical complementary of DNA and steroid agonists and antagonists.
Modelling studies in our laboratories over the past decade have demonstrated that a variety of natural products exhibit stereochemical complementarity with nucleic acids. In the case of steroid hormones, the basic cyclopentanophenanthrene skeleton fits between base pairs in partially unwound double stranded DNA; heteroatoms on the steroids form stereospecific donor/acceptor linkages to hydrogen bonding heteroatoms on the DNA. Each of the hormones appears to fit best in the site, i.e. 5'-dTdG-3'.5'dCdA-3'; the pattern of donor/acceptor linkages is unique for each type of hormonal activity. Steroid hormone agonists fit into the same site as the parent hormone; degree of fit correlates with degree of hormonal activity. Steroid hormone antagonists (e.g. RU 486; tamoxifen; anandron) fit into the same site as the agonists but possess different donor/acceptor linkages than the parent hormone; these linkages occur within the site between the base pairs or along the outside surface of the DNA helix in the major or minor grooves. A chronological review of the underlying concepts and observations leading to these discoveries is presented. Work in progress and some potential implications of the emerging technology are also discussed.
Hendry
L B
LB
Department of Medicine, Medical College of Georgia, Augusta 30912.
D004247:DNA; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D013256:Steroids / Q000037:antagonists & inhibitors*
D013256:Steroids; D004247:DNA