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DOCKING OF STRUCTURALLY RELATED DIOLEPOXIDES OF BENZO(GHI)FLUORANTHENE WITH DNA
Citation:
Overly, K. R., F. J. Coughlin, A. McIntyre, J. R. Rabinowitz, AND B. P. Cho. DOCKING OF STRUCTURALLY RELATED DIOLEPOXIDES OF BENZO(GHI)FLUORANTHENE WITH DNA. Presented at American Assoc. of Cancer Research Mtg, Washington, DC, 07/11-14/03.
Description:
Docking of structurally-related diolepoxides of benzo{ghi}fluoranthene and benzo{c}phenanthrene with DNA
Polycyclic aromatic hydrocarbons are a class of chemicals found in the environment. Some class members are potent carcinogens while others with similar structures show little activity after considerable testing. Metabolic activation to reactive diolepoxides (DEs) followed by binding to DNA is a putative mechanism for causing DNA lesions. Evidence indicates that molecular deformity and diol conformation play an important role in determining activity. We proposed (Chem. Res. Toxicol.. 15, 198-208 (2002)) that the pseudo-diaxial diol conformation of DEs has more favorable electrostatic interactions in the minor groove of DNA than the pseudo-diequatorial DEs, yielding greater reactivity with dG ('diol hypothesis'). To explore this hypothesis, geometries of the anti and syn-DEs of benzo{c}phenanthrene (B{c}P) and its planar analog benzo{ghi}fluoranthene (B {ghi }F) were initially optimized with molecular mechanics methods and refined further with quantum mechanical methods. The most stable structures obtained for syn- and anti-B{c}PDE are pseudo-diequatorial. In contrast, the structure obtained for anti-B{ghi }FDE is pseudo-diequatorial while the syn-isomer is pseudo-diaxial. These structures were docked into canonical B-DNA using AutoDock. Each DE was flexibly docked with a 5'-CGCGAATTCGCG-3' B-DNA. The most stable docking mode for all of the DEs is in the minor groove. B{c }PDEs dock near the GA and TC regions with the most stable dockings having hydrogen bonds to a GC pair. The arene rings of the B {c }PDEs lie parallel to the DNA backbone oriented toward the AATT region. Anti-B{ghi }FDE dockings are similar to that of the B{c}PDEs with hydrogen bonds to GC pairs but with less selectivity with respect to the orientation of the aromatic rings. Dockings of the pseudo-diaxial syn-B {ghi }FDEs occur in the same region of the strand as the other DEs but with greater specificity. Syn-B {ghi }FDE forms a trio of hydrogen bonds with the epoxide bonded to a dG amino group and the hydroxyls forming bridge between the DNA backbones. A second set of docking experiments examined the minor groove versus major groove preference of each of the DEs when docked with 5'-CGCGAATT-3' B-DNA. The shorter DNA segment allows for the exclusion of much of the minor groove from the docking grid. A 0.53-0.92 kcal/mol preference was found for the minor groove over the major groove. Sequence dependence of the docking modes and docking of the benzylic carbocations derived from the DEs will be discussed.