INVESTIGATION OF THE INTERACTION OF ISTAROXIME WITH TOPOISOMERASE ENZYMES

The gene transfer and information exchange of living organisms are carried out by DNA replication with the help of topoisomerase enzymes. DNA topoisomerase enzymes are of great importance for the survival of living organisms. For this reason, topoisomerases have become the target of the anticancer drug research. In this study, one of the Sarco- endoplasmic reticulum Ca2+-ATPase (SERCA2a) inhibitor, Istaroxime is investigated. The compound took attention by having antitumor activity and being particularly
effective at prostate cancer cells. Sercoplasmic endoplasmic Ca2+ ATPase (SERCA), is a potential anti-cancer target because of its important role in cellular Ca2+ regulation, cell proliferation and apoptosis. In addressing this compound, there are notable factors like having a 2a isomerism as well as being a Sercoplasmic endoplasmic reticulum calcium ATPase inhibitor. Since SERCA2a inhibitors are more abundant in cardiomyocytes, toxic effects are less or not seen compared to other topoisomerases and SERCA inhibitors. The main purpose of the study, was to examine the possible interaction of Istaroxime with topoisomerase enzymes. The determination of the interaction between the compound and topoisomerase enzymes indicates, Istaroxime has the possibility to be a topoisomerase enzyme inhibitor and therefore to be a potential anticancer agent. Due to the need for topoisomerase II inhibitors with less side- effects and less toxic properties, we evaluated if Istaroxime could be a topoisomerase II inhibitor. In this study, molecular docking method, which is one of the computer-based drug design methods, was used. The molecular docking method demonstrates the docking of the ligand and the receptor protein in the appropriate conformation on the basis of key-lock compatibility in the computer environment. Interaction analysis of Istaroxime (ZINC04392967) and topoisomerase type IIA enzyme (PDB code: 4fm9) was perfomed by AutoDockVina program on molecular docking process Pyrx and the results were evaluated. In line with the approximate values obtained, it was observed that Istaroxime gave a close binding affinity with Etoposide, a known topoisomerase II enzyme inhibitor, which we used as a control compound. As a result of these analyzes, we investigated if Istaroxime can perform a similar coupling with Etoposide and therefore may have a high potential to inhibit the topoisomerase type IIA enzyme. According to our in vitro enzyme activity test results, we showed that istaroxime is a topoisomerase I inhibitor but not a topoisomerase II inhibitor. Given these results, it is likely that more detailed studies of Istaroxime are needed in anticancer studies.