title: Effect of steroids on DNA synthesis in an in vitro replication system: initial quantitative structure-activity relationship studies and construction of a non-estrogen receptor pharmacophore.
abstract: The molecular mechanism(s) by which steroids affect carcinogenesis is an active area of investigation. Recent studies with a series of related steroids in an in vitro DNA replication system produced a wide range of effects including enhancement and inhibition of DNA synthesis. The HeLa cell-free system used in these studies did not contain estrogen receptors. Since the majority of hormone effects on cellular replication have been attributed to interactions with estrogen receptors, an alternative description of the results was required. Quantitative structure-activity relationships (QSARs) were used to relate the observed bioactivity of these steroids with their structure. The results indicate that the percentage of DNA replication could be related to three parameters according to the following equation: %DNA = 23.9(+/-3.8)Xdipact + 57.8(+/-22.4)Hyd - 19.4(+/-10.4)Biophpi + 128.9, where Xdipact is the dipole moment on the X-axis, Hyd is the atomic hydrophobicity index, and Biophpi is the atomic pi population on the heteroatom found in the pharmacophore. For each molecule, the orientation of the functional groups changed the dipole moment value, and this descriptor was used as a selector of active conformations. A 3D-QSAR model was then constructed combining pharmacophoric features and global properties, and the active space and inactive space were defined using a Boolean volumetric operation.
authors.affiliation: Department of Oncology, Pharmacokinetics Division, Department of Pharmacology and Therapeutics, and Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Azzaoui
authors.forename: M J
authors.initials: MJ
authors.lastname: Diaz-Perez
authors.forename: M
authors.initials: M
authors.lastname: Zannis-Hadjoupoulos
authors.forename: G B
authors.initials: GB
authors.lastname: Price
authors.forename: I W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011987:Receptors, Steroid; D013256:Steroids; D004247:DNA