Structural basis of DNA topoisomerase II-α (Top2-α) inhibition: a computational analysis of interactions between Top2-α and its inhibitors

Topoisomerases are enzymes that resolve winding problem of DNA during cellular processes. Because of essential roles of these enzymes in maintenance of cell function, topoisomerases are important targets for cancer chemotherapy. To date, several topoisomerase inhibitors have been introduced and applied as drugs in the treatment of cancer. Topoisomerase II alpha (Top2-alpha), a subclass of topoisomerase II enzymes, functions as the target for several anticancer agents and a variety of mutations in this protein have been associated with the development of drug resistance. Mitoxantrone and Amsacrine are among two important inhibitors of Top2 enzymes used in cancer chemotherapy. In this study, we used computational methods to analysis interactions between these compounds and Top2-alpha in order to identify the most important residues involved in the enzyme inhibition. In order to obtain reliable results, several docking studies have been performed on the human Top2-beta to reproduce binding modes which are observed in the crystal form of Top2-beta complexed with Mitoxantrone and Amsacrine. Since human Top2-beta is the closest homologue to Top2-alpha, same docking parameters have been used for docking of Top2-alpha with mentioned drugs. The data also showed that the main residues involved in the interaction between Top2-alpha and Mitoxantrone were Lys489, Asp504, Glu506, Gly488, Ile490 and Leu491. For Top2 alpha-Amsacrine complex, the interaction was mainly through Arg487, Glu506, Gly488, Lys489, Asn504 and Ala505. These findings clarify the mechanisms of action for these drugs and may facilitate future drug development and cancer treatment.