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Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study

Fung-Ming Siu1, Yves Pommier

  • 1Center for High Performance Computing, Institute of Advanced Computing and Digital Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Boulevard, University Town of Shenzhen, Xili Nanshan, Shenzhen 518055, China, Department of Chemistry and Institutes of Molecular Technology for Drug Discovery and Synthesis, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Nucleic Acids Research
|September 12, 2013
PubMed

Insights

Topoisomerase I (Top1) inhibitors show sequence selectivity, crucial for therapeutic targeting. Molecular dynamics revealed drug binding energies and linker domain dynamics drive this selectivity, with specific nucleotide interactions being key.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Computational Chemistry

Background:

  • Topoisomerase I (Top1) inhibitors, like camptothecin (CPT), stabilize the Top1-DNA cleavage complex.
  • The sequence selectivity of these inhibitors is vital for targeting specific therapeutic genomic sites.
  • Underlying molecular mechanisms of Top1 inhibitor sequence selectivity are not well understood.

Purpose of the Study:

  • To elucidate the structural, dynamic, and energetic factors contributing to Top1 inhibitor sequence selectivity.
  • To understand the molecular basis for differential sequence selectivity among Top1 inhibitors.

Main Methods:

  • Molecular dynamics (MD) simulations were employed to analyze Top1 inhibitor-DNA interactions.
  • Per-residue binding energy analysis was used to identify key molecular interactions.
  • Potential of Mean Force (PMF) analysis investigated drug dissociation mechanisms.

Main Results:

  • CPT sequence selectivity strongly correlates with drug binding energies and linker domain dynamics.
  • Non-polar interactions between CPT and the +1 nucleotide significantly contribute to binding energy.
  • Drug dissociation, analyzed via PMF, is implicated in sequence selectivity.

Conclusions:

  • Molecular dynamics simulations reveal key determinants of Top1 inhibitor sequence selectivity.
  • Understanding these mechanisms aids in explaining differential selectivity, such as between CPT and LMP-776.
  • This research provides a foundation for designing more targeted Top1 inhibitor therapies.

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