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.

Keywords

• Anthracycline cardiotoxicity
• cardioprotective agents
• dexrazoxane
• in silico analysis
• topoisomerase II inhibitors

DEKSRAZOKSANIN OLASI KARDİYOPROTEKTİF ETKİ MEKANİZMASI VE MUHTEMEL İNSAN TOPOİZOMERAZ IIΒ İNHİBİTÖRLERİ: İN SİLİCO ANALİZ

Abstract

Amaç: Bu çalışmanın amacı deksrazoksanın kardiyoprotektif etkisinde hangi metabolitinin rol oynadığını belirlemek ve ayrıca deksrazoksanın klinik kullanımı sınırlı olduğu için deksrazoksana alternatif bileşikleri saptamaktı. Bu amaçla, deksrazoksan ve üç metabolitinin (B, C, ve ADR-925) ve ayrıca literatürde topoizomeraz VI (insan DNA topoizomeraz II beta’nın prototipi) için inhibitör olduğu bildirilen bileşiklerin insan DNA topoizomeraz II beta ile etkileşimleri moleküler kenetleme ile araştırıldı. Sonrasında tüm bu bileşiklerin teorik ADMET özellikleri belirlendi.

Gereç ve Yöntem: Moleküler yapılar Gaussview 05 ve Gaussian 03 paket programları ile optimize edildi. Moleküler kenetleme çalışmaları için AutoDock 4.2 yazılımı kullanıldı ve kenetleme kompleksleri Discovery Studio Client 4.1 programı kullanılarak 2D ve 3D olarak analiz edildi. Teorik ADMET parametrelerini hesaplamak için pkCSM çevrimiçi programı kullanıldı.

Sonuç ve Tartışma: Moleküler kenetleme çalışmaları sonucunda deksrazoksanın B metabolitinin, hem deksrazoksana hem de diğer metabolitlerine kıyasla insan DNA topoizomeraz II beta’ya daha fazla bağlanma potansiyeli olduğu belirlendi. Literatürde bildirilen diğer bileşiklerin de insan DNA topoizomeraz II beta’ya bağlanma potansiyelleri sırası ile radisikol>kinakrin>purpurin>9-Aminoakridin>heksilresorsinol şeklindeydi.

Sonuçlar, deksrazoksanın antrasiklin kardiyotoksisitesine karşı kardiyorprotektif etki mekanizmasında deksrazoksanın B metabolitinin önemli bir rol oynadığını göstermiştir. Bunun yanında, araştırılan diğer bileşiklerden purpurin dışındakilerin toksisite oluşturma potansiyelleri olduğu da belirlenmiştir. 

Keywords

• Antrasiklin kardiyotoksisitesi
• deksrazoksan
• in siliko analiz
• kardiyoprotektif ajanlar
• topoizomeraz II inhibitörleri

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