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

Jing Yang; Jing Chen; Zibiao Li

doi:10.1071/CH15624

RESEARCH FRONT

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

Jing Yang ^A , Jing Chen ^B ^D and Zibiao Li ^C ^D

+ Author Affiliations

- Author Affiliations

^A Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Republic of Singapore.

^B Experimental Center, Yunnan University of Traditional Chinese Medicine, Yuhua Road, #1076, Chenggong District, Kunming, Yunnan 650500, China.

^C Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research), 2 Fusionopolis Way, Innovis, #09-52, Singapore 138634, Republic of Singapore.

^D Corresponding authors. Email: sunnychenj@163.com; lizb@imre.a-star.edu.sg

Australian Journal of Chemistry 69(4) 379-387 https://doi.org/10.1071/CH15624
Submitted: 6 October 2015 Accepted: 6 November 2015 Published: 25 November 2015

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.

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

Abstract

References

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