Molecular modeling of diastereoisomeric aggregates of l/d ser/histamine amide with 5'-TpTpdC-3'.

Novel nonpeptide serine/histamine amides (1: l-Ser-Hism,2: d-Ser-Hism) with potent DNA cleavage activity were designed. Conformational analysis and docking study were carried out in an attempt to understand the DNA cleavage mechanism of the designed enantiomeric nonpeptides. First, the most stable conformers of the designed amides were obtained from the conformational analysis by random search. Next, the three-dimensional structures of l-Ser-Hism.5'-TpTpdC-3' and d-Ser-Hism.5'-TpTpdC-3' complexes were built using molecular docking techniques. The docked diastereoisomeric aggregates show that both l-Ser-Hism and d-Ser-Hism bind to two neighboring phosphates in the 5'-TpTpdC-3' backbone through H-bonds. This binding mode suggests a possible phosphodiester bond hydrolysis mechanism. In addition, the binding energies of two constructed complexes were also calculated with the Tripos force field. It indicates that the binding ability between l-Ser-Hism and 5'-TpTpdC-3' is stronger than that of d-Ser-Hism, suggesting a stronger DNA cleavage activity of l-Ser-Hism than that of d-Ser-Hism. The results agree with our experimental DNA cleavage assays. Supplementary material is available for this article if you access the article at http://dx.doi.org/10.1007/s00894-002-0114-9. A link in the frame on the left on that page takes you directly to the supplementary material. Figure Docking structures of1 and2 binding with oligonucleotide: l-Ser-Hism.5'-TpTpdC-3'(left), d-Ser-Hism.5'-TpTpdC-3'(right). Hydrogen bonds are shown in dotted lines. Only one strand of the oligonucleotide is shown for clarity