Possible Cardioprotective Mechanism of Action of Dexrazoxane, and Probable Human Topoisomerase Iiβ Inhibitors: an in Silico Analysis

Abstract

Objective: The aim of this study was to determine which metabolite plays a role in the cardioprotective effect of dexrazoxane, and also to identify alternative compounds to dexrazoxane since clinical use of dexrazoxane is limited. For this purpose, the interactions of dexrazoxane and its three metabolites (B, C, and ADR-925), as well as the compounds, which reported to be inhibitors for topoisomerase VI (prototype of human DNA topoisomerase II beta), with human DNA topoisomerase II beta were investigated by molecular docking. Afterwards, the theoretical ADMET properties of all these compounds were determined Material and Method: The molecular structures were optimized by Gaussview 05 and Gaussian 03 package programs. AutoDock 4.2 software was used for molecular docking studies and the docking complexes were analyzed in 2D and 3D using the Discovery Studio Client 4.1 program. The pkCSM online program was used to calculate the theoretical ADMET parameters. Result and Discussion: As a result of molecular docking studies, it was determined that the B metabolite of dexrazoxane has a higher binding potential to human DNA topoisomerase II beta compared to both dexrazoxane and its other metabolites. The binding potentials of other compounds reported in the literature to human DNA topoisomerase II beta were radicicol>quinacrine>purpurin>9-Aminoacridine>hexylresorcinol, respectively. The results showed that the B metabolite of dexrazoxane plays an important role in the cardioprotective mechanism of action of dexrazoxane against anthracycline cardiotoxicity. In addition, it has been determined that other compounds, except purpurin, have the potential to cause toxicity. © 2022 University of Ankara. All rights reserved.