title: Evidence for the contribution of non-covalent steroid interactions between DNA and topoisomerase in the genotoxicity of steroids.
abstract: Fifty two steroids and 9 Vitamin D analogs were docked into ten crystallographically-defined DNA dinucleotide sites and two human topoisomerase II ATP binding sites using two computational programs, Autodock and Surflex. It is shown that both steroids and Vitamin D analogs exhibit a propensity for non-covalent intercalative binding to DNA. A higher predicted binding affinity was found, however, for steroids and the ATP binding site of topoisomerase; in fact these drugs exhibited among the highest topo II binding observed in over 1370 docked drugs. These findings along with genotoxicity data from 26 additional steroids not subjected to docking analysis, support a mechanism wherein the long known, but poorly understood, clastogenicity of steroids may be attributable to inhibition of topoisomerase. A "proof of principle" experiment with dexamethasone demonstrated this to be the likely mechanism of clastogenicity of, at least, this steroid. The generality of this proposed mechanism of genotoxicity across the steroids and vitamin-D analogs is discussed.
authors: RDS Consulting Services , 3335 Grand Falls Blvd, Maineville, OH , United States and.
authors: Ronald D
authors: RD
authors: Snyder
authors: Patrick A
authors: PA
authors: Holt
authors: Jon M
authors: JM
authors: Maguire
authors: John O
authors: JO
authors: Trent
mesh_terms: D001665:Binding Sites; D003461:Crystallography / Q000379:methods; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D009152:Mutagenicity Tests; D012984:Software; D013256:Steroids / Q000378:metabolism / Q000633:toxicity*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*
chemical_list: D013256:Steroids; D014807:Vitamin D; D004247:DNA; D004250:DNA Topoisomerases, Type II
keywords: Aqueous solubility; DNA intercalation; docking studies