Structural Basis for the Structure–Activity Behaviour of Oxaliplatin and its Enantiomeric Analogues: A Molecular Dynamics Study of Platinum-DNA Intrastrand Crosslink Adducts

Abstract

The discrimination of Pt-GG adducts by mismatch repair proteins, DNA damage-recognition proteins, and translation DNA polymerases was thought to be vital in determining the toxicity, efficacy, and mutagenicity of platinum anti-tumour drugs. Studies on cis-diammine-Pt-GG (from cisplatin and carboplatin) and trans-R,R-diaminocyclohexane (DACH)-Pt-GG indicated that these proteins recognized the differences in conformation and conformational dynamics of Pt-DNA complexes. However, the structural basis of enantiomeric DACH-Pt-GG forms is unclear. Molecular dynamics simulations results presented here reveal that the conformational dynamics between trans-R,R-DACH-Pt-GG, trans-S,S-DACH-Pt-GG, cis-DACH-Pt-GG and undamaged DNA are distinct and depend on the chirality of DACH though their major conformations are similar. Trans-DACH-Pt was found to be energetically favoured over cis-DACH-Pt to form DNA adducts. Moreover, oxaliplatin and its cis-DACH analogues were found to preferentially form hydrogen bonds on the 3′ side of the Pt-GG adduct, whereas the S,S-DACH-Pt preferred the 5′ side. A three-centre hydrogen bond formed between cis1-DACH-Pt and DNA was observed, and the differences in hydrogen bond formation are highly correlated with differences in DNA conformational dynamics. Based on these results, it is suggested that the different bioactivities of oxaliplatin and its enantiomeric analogues were controlled by the difference in hydrogen bonds formation dynamics between DNA and the Pt moiety. Our molecular dynamics approach was demonstrated to be applicable to the study of stereoisomer conformations of platinum-DNA model, thereby suggesting its potential application as a tool for the study and design of new effective platinum-based drugs.