title: Modelling the interaction of cisplatin with DNA.
abstract: Molecular mechanics modelling of the interaction of the anti-cancer drug cisplatin (cis-[Pt(NH3)Cl2]) and its congeners with adjacent purines of double stranded DNA fragments is described. When the cis-Pt(NH3)2 moiety binds to the N7 atoms of adjacent guanine residues, two hydrogen bonds form between the ammine ligands and the DNA. One is to a phosphate oxygen on the 5' side of the GpG pair, and the other is to the O6 atom of the guanine on the 3' side. The observation of these two hydrogen bonds can be correlated with the inactivity of cisplatin congeners lacking ammine hydrogen atoms. When, in the binding, the ammine ligands are replaced by chiral bidentate ligands, such as R,R- or S,S-cyclohexane-1,2-diamine, the calculations predict a chiral discrimination of the order of 10 kJ mol-1. To investigate why cisplatin binds to ApG sequences but not to GpA sequences of DNA, the interaction of cisplatin with d(GpApG):d(CpTpC) and d(GpGpA):d(TpCpC) sequences was modelled. The calculations indicate that, in the former case, both of the hydrogen bonds are able to form, but that, in the latter case, the second of the hydrogen bonds is replaced by a highly unfavourable interaction between ligand NH3 and adenine NH2 groups. Thus an explanation of the differential binding to ApG and GpA sequences is provided.
authors.affiliation: School of Chemistry, University of Sydney, Australia.
authors.forename: T W
authors.initials: TW
authors.lastname: Hambley
mesh_terms: D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004273:DNA, Neoplasm; D002945:Cisplatin