This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Thalidomide possesses unique immunosuppressive and anti-inflammatory properties that make it a promising drug for the treatment of cancers and other diseases. However, it also causes serious genetic damage, and the molecular-level details of its activity remains unknown. To elucidate the thermodynamics driving nucleic acid damage by thalidomide, we are conducting a computational study of the interaction between thalidomide and 12-bp polynucleotides (one full turn). Our preliminary results prove that although thalidomides arrangement of hydrogen bond donors and acceptors is similar to those in the bases of nucleic acids, the strength of the interaction is insufficient to compete with the Watson-Crick base pairing. Also, thalidomides benzene ring can slide between neighboring base pairs and interact favorably with DNA via pi-stacking, so we are confident that thalidomide interacts with nucleic acids via intercalation. We will use the MD module of the NWChem computational chemistry program equilibrate thalidomide-nucleic acid structures. The highly charged nature of nucleic acids requires up to 10 ns for full equilibration, which exceeds the limitations of our own computational resources. Our efforts will be benchmarked against experimental results which show that 1) guanine-rich regions are more susceptible to thalidomide damage, and 2) the S-enantiomer of thalidomide does more damage than the R-enantiomer. We expect that the structures of the bound systems will reflect this trend, and we will follow up with electrostatic and solvation free energy calculations that will quantify the binding of thalidomide to nucleic acids.
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