A computational model for targeting nucleic acids: Estimating changes in free energy of drugs in complex with RNA and variable sequences of DNA

Anthracycline antibiotics, such as doxorubicin and daunorubicin, bind to DNA and interfere with the process of transcription, and are some of the most common anticancer agents in use today. The design of novel drugs with specificity towards a specific sequence of nucleotide base pairs of DNA, or a specific RNA structure, could have significant therapeutic impact. Furthermore, with the knowledge gained from identifying specific sequences of genes from the Human Genome Project, a novel drug could be identified with the hopes of modifying gene expression or protein synthesis.; In the first two studies, methods were tested utilizing the computational chemistry program HINT (Hydropathic INTeractions) to estimate the free energy and characterize the types of binding interactions of 14 aminoglycoside antibiotics with 16S ribosomal RNA. Another study was conducted to predict the binding of the dye compound Hoechst 33258 with a sequence of double-stranded mRNA containing a ‘CC’ base pair mismatch. The results of these studies demonstrate the usefulness of several molecular modeling techniques, most notably the HINT program, in predicting the binding interactions of complexes of drugs with the nucleic acid RNA.; Most of this research involves methods for the prediction of the binding interactions of complexes of anthracyclines with DNA. The first of these studies calibrates the use of the HINT model for modeling these compounds with known experimental binding data. While there are two notable discrepancies in these calculations with the experimental data, specifically in modeling the C 14 hydroxyl and the N3′ ammonium interactions, there was a good agreement overall. These initial calculations led to a more comprehensive molecular modeling analysis of the sequence specificity of a broad sampling of 65 doxorubicin analogs, obtained from a 3-Dimensional search of the NCI database. HINT was used to predict the free energy for each analog with a variety of 8 DNA sequences, and a ΔΔG was obtained for the binding of each sequence versus the highest binding sequence. The free energy contribution of the various functional groups of these compounds was also analyzed. The results of this study demonstrate that there are potentially some significant sequence specific binding differences for several doxorubicin analogs with different structural features that are worthy of future analysis.