Topoisomerase II resolves topological complications of DNA introduced through cellular processes such as replication, transcription, and chromosomal condensation. This enzyme is an attractive anticancer target, owing in part to its indispensability for proliferation of tumor cells. Only this year has three dimensional structural information concerning eukaryotic topoisomerase II become available. This advance makes possible structure-based drug design efforts toward novel anticancer agents. New anti-topoisomerase agents are desirable given the toxicity and resistance of many topoisomerase-targeting anticancer drugs. Several major conformational changes which occur in the topoisomerase catalytic cycle are amenable to computational exploration. We employ automated molecular docking techniques to identify putative ligands from a database of commercially available compounds. These ligands are selected for their ability to inhibit gross molecular rearrangements that would render topoisomerase ineffective or trap a covalent enzyme-DNA intermediate. The strength of molecular docking lies in its ability to identify structurally and chemically novel inhibitory frameworks. Inhibitor candidates are assayed experimentally for the ability to prevent relaxation of DNA, and experiments are proposed to verify the predicted mode of drug binding and mechanism of action. The MidasPlus display software, a software package developed and maintained by the Computer Graphics Lab, is instrumental in reviewing proposed inhibitor candidates. This software package makes visualization of complex molecular scenes rapid and effective, much more so than with other display software.
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