THE INTERACTION BETWEEN THE NOVEL INTERCALATOR DIETHIDIUM CATION AND B-FORM DNA - A THEORETICAL-STUDY

This research is an effort to further understand the physicochemical i nteraction between the novel drug molecule diethidium (2,7-diamino 9-[ 2,7 diamino 10-nN- phenanthridium] 10-nN- phenanthridium) and its biol ogical receptor DNA. The ultimate goal is the elucidation of this nove l class of drugs as potential pharmaceutical agents. Understanding the physicochemical properties of this drug as well as the mechanism by w hich it interacts with DNA should ultimately allow the rational design of novel anti-cancer or anti-viral drugs. A novel binding structure f or the diethidium cation to B-form DNA is herein described. Molecular modeling on the complex formed between diethidium and a dodecamer of d ouble-stranded B-form DNA, CGCGAATTCGCG, has shown that this complex i s indeed fully capable of participating in the formation of a stable i ntercalation site. It was expected that diethidium would have a mechan ism of intercalation significantly different from other classical inte rcalators because a) Its structure, that of two perpendicular planes, each known to have excellent intercalation properties, is novel b) The linker region length is zero c) The tilt between the two planes of th e drug matches the geometry of the space available to this drug in the major groove. We have studied the complex formed when diethidium ente rs the central site of the B-DNA dodecamer through the major groove. T he complex forms several classes of intercalation structures, which ar e all stable and vary from ''partially intercalated'' to ''fully inter calated''. Multiple minimizations show the drug to be very mobile with in the intercalation site. Further, some structures show organization and concomitant stiffening of the DNA above the intercalation site, wi th a disorganization and disruption of the regular B-DNA structure imm ediately below the intercalation site. This particular phenomena may b e expected to lead to significantly different physicochemical properti es for the diethidium complex with respect to other known intercalator s, because this sort of vectorial difference in structure above and be low the site of intercalation is unknown in existing intercalators, as far as the authors are aware. In addition, we expect the mechanism of interaction between drug and DNA to be described by ''direct ligand t ransfer'', wherein the drug is transferred from duplex DNA to duplex D NA without re-entering the solvent.(1) This work is the first instance known to the authors of a novel drug entity that was deduced solely b y mathematical reasoning(2) and described subsequently by computationa l methods. Evidence that diethidium should interact with its target si te DNA differently from other known intercalators is strong.