Interaction of Mitoxantrone and its Analogs with Methylated and Non-Methylated CpG Islands in Tetrameric DNA Sequences: A Molecular Modeling Study

Many genetic and environmental factors contribute towards the growth of cancer but DNA methylation may provide a link between these influences. DNA methylation maintains the genome stability and protects against tumor formation. Mitoxantrone is a well known drug having anti cancer action with relatively reduced cardiotoxicity as compared to other anthracycline drugs. The present study is an effort to understand the interaction of ligands – mitoxantrone, ametantrone, AmidoI, AmidoII, CH3, and NSC analogs, differing from each other in position of side chain or substituent groups on the chromophore, with four methylated tetrameric sequences, d-(AmeCAG)2, d-(AmeCGC)2, d(AmeCGG)2, and d-(AmeCGT)2 and corresponding non methylated tetranucleotides that is, d-(ACAG)2, d-(ACGC)2, d-(ACGG)2, and d-(ACGT)2 using molecular modeling tools. We have carried out the computer simulation of uncomplexed DNA as well as their complex formed by intercalation of aromatic chromophore of ligand within the methylated/non-methylated CpG/CpaA site in explicit water medium using Molecular Operating Environment (MOE) software tool on Sun Solaris platform. The total potential energy, interaction energy and various other components of energy obtained on binding of these ligands to the DNA sequences have been determined. The structural changes in drug as well as in DNA as a result of interaction have been examined extensively. The results show that mitoxantrone is capable of forming stable complex with all methylated and non-methylated CpG/CpA tetrameric DNA sequences. The conformation of the minimum energy complex has been analyzed.