Mutual Conformational Adaptation of Both Ligand and Receptor in Antitumor Drug-DNA Complexes

摘要: Many antitumor/anticancer drugs bind and interact with DNA double helix to exert their biological activities. The consequence of the binding process is that both drug molecule change conformations accommodate each other optimize interactions. Two series drug-DNA complexes associated intercalator minor-groove binder, structures derived from high resolution x-ray diffraction analysis, are used illustrate this concept mutual conformational adaptation between ligand receptor. Anthracylcine drugs, including daunomycin, adriamycin nogalamycin, intercalate CpG base pairs using aglycone chromophore its elongated direction almost perpendicular Cl’-Cl’ vector neighboring pairs. Around anthracycline intercalator, stretches two complementary backbones in a different manner move 6.8 A apart. On one side, dC changes e/ζ combinatory torsion angles ~[-100°/180°], while keeping glycosyl χ angle near anti range [-90°]. all maintained close those B-DNA exception changing normal [ca. -150°]. All sugar puckers C2’- endo family. Daunomycin adjust ether linkage (between ring amino sugar) such fits better minor groove. In contrast, nogalamycin has gentle bend long chromophore, bringing aminoglucose nogalose closer other. groove dodecamer complexes, there wide backbone molecules despite uniform narrow width central AT sequences. Drug (netropsin, distamycin Hoechst 33258) exhibit sufficient flexibility follow contour surface right-handed