The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: Molecular dynamics simulations

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor c ompounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficien t condition for antitumor activity of these compounds. Rational design of n ew compounds of this chemotype requires knowledge about the structure of th e intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) m ay provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and positio n of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GC GCGCGCGCGC)(2). The orientation of the side chain in relation to the ring s ystem is determined by the position of its attachment. Orientation of the r ing system inside the intercalation cavity depends on the number and positi on of side chain(s). The conformations of the side chain(s) of all. PATs st udied in the intercalation complex were found to be very similar to those o bserved in water.