The anticancer drug bleomycin investigated by density functional theory

Abstract

Activated bleomycin (ABLM) is an oxygenated iron drug complex which embodies the drug's DNA-cleaving activity. This activity is exercised on DNA, if present, but if DNA is absent, the drug itself is inactivated. We have employed quantum density functional theory (DFT)-based methods to investigate (i) the structure of the Fe(II)BLM complex that is first formed in the human body after drug's administration, and (ii) the activation mechanism of the O–O bond present in the ABLM. We have identified the controversial second axial ligand as the endogenous oxygen atom of the carbamoyl group. Our first principles molecular dynamics (MD) simulations indicate a homolytic cleavage as the mechanism of the O–O bond activation in the ABLM complex.

Keywords:

• Bleomycin
• O–O bond activation
• Density functional theory
• Car–Parrinello molecular dynamics simulations
• Iron–oxo complex

Acknowledgements

We thank Prof. U. Roethlisberger and members of her group at EPFL for providing and introducing us to the QM/MM hybrid code. We acknowledge the CYTTRON consortium for partially financing this project. The use of supercomputer facilities was sponsored by the Stichting Nationale Computer Faciliteiten (NCF), with financial support from Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).