Disturbance of DNA conformation by the binding of testosterone-based platinum drugs via groove-face and intercalative interactions: a molecular dynamics simulation study.

Shanshan Cui,Yan Wang,Guangju Chen

doi:10.1186/1472-6807-13-4

Abstract

BackgroundTo explore novel platinum-based anticancer agents that are distinct from the structure and interaction mode of the traditional cisplatin by forming the bifunctional intrastrand 1,2 GpG adduct, the monofunctional platinum + DNA adducts with extensive non-covalent interactions had been studied. It was reported that the monofunctional testosterone-based platinum(II) agents present the high anticancer activity. Moreover, it was also found that the testosterone-based platinum agents could cause the DNA helix to undergo significant unwinding and bending over the non-testosterone-based platinum agents. However, the interaction mechanisms of these platinum agents with DNA at the atomic level are not yet clear so far.ResultsIn the present work, we used molecular dynamics (MD) simulations and DNA conformational dynamics calculations to study the DNA distortion properties of the testosterone-based platinum + DNA, the improved testosterone-based platinum + DNA and the non-testosterone-based platinum + DNA adducts. The results show that the intercalative interaction of the improved flexible testosterone-based platinum agent with DNA molecule could cause larger DNA conformational distortion than the groove-face interaction of the rigid testosterone-based platinum agent with DNA molecule. Further investigations for the non-testosterone-based platinum agent reveal the occurrence of insignificant change of DNA conformation due to the absence of testosterone ligand in such agent. Based on the DNA dynamics analysis, the DNA base motions relating to DNA groove parameter changes and hydrogen bond destruction of DNA base pairs were also discussed in this work.ConclusionsThe flexible linker in the improved testosterone-based platinum agent causes an intercalative interaction with DNA in the improved testosterone-based platinum + DNA adduct, which is different from the groove-face interaction caused by a rigid linker in the testosterone-based platinum agent. The present investigations provide useful information of DNA conformation affected by a testosterone-based platinum complex at the atomic level.

Highlights

To explore novel platinum-based anticancer agents that are distinct from the structure and interaction mode of the traditional cisplatin by forming the bifunctional intrastrand 1,2 GpG adduct, the monofunctional platinum + DNA adducts with extensive non-covalent interactions had been studied
Disturbance of DNA conformation by the binding of Pt (Testo)(II) agent via groove-face interaction Conformation analysis of Pt(Testo)(II) + DNA adduct Based on the results of previous experiment [27], the testosterone-based platinum agent, cis-[Pt(NH3)2(17αpyridyl-3-ethynyltestosterone)Cl]+ (called Pt(Testo)(II)), which consists of testosterone, ethynyl linker and platinum(II) center coordinated by one chlorine atom and three nitrogen atoms from two ammonias and one pyridyl, as an efficient anticancer agent, binding to a DNA molecule (called Pt(Testo)(II) + DNA adduct), was tested by molecular dynamics (MD) simulation
It is demonstrated from this average structure that the testosterone with a groove-face interaction mode locates at the major groove of DNA molecule; the platinum center binds to the N7 atom of G15 base of DNA molecule; the pyridyl ring is perpendicular to the plane of G15 base of DNA; the plane of testosterone with the rigid ethynyl (–C ≡ C–) linker is perpendicular to the pyridyl ring and plane of T14:A27 base pair of DNA molecule

Summary

Introduction

To explore novel platinum-based anticancer agents that are distinct from the structure and interaction mode of the traditional cisplatin by forming the bifunctional intrastrand 1,2 GpG adduct, the monofunctional platinum + DNA adducts with extensive non-covalent interactions had been studied. Much effort has been devoted to the developments of novel platinum-based anticancer agents which might form monofunctional platinum + DNA adducts with extensive non-covalent interactions to circumvent such drawbacks [11,15,16]. The structures of these monofunctional platinum + DNA adducts with extensive non-covalent interactions are different from that produced by cisplatin [8,9]. The systematic studies on the relationship between the ligand properties of platinum agents and interaction modes in the platinum + DNA adducts have not yet been clearly detailed so far

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Conclusion