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The Strathprints institutional repository is a digital archive of University of Strathclyde research outputs.

Strathprints serves world leading Open Access research by the University of Strathclyde, including research by the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), where research centres such as the Industrial Biotechnology Innovation Centre (IBioIC), the Cancer Research UK Formulation Unit, SeaBioTech and the Centre for Biophotonics are based.

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Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics

Clark, R.L. and Deane, F.M. and Anthony, N.G. and Johnston, B.F. and McCarthy, F.O. and Mackay, S.P. (2007) Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics. Bioorganic and Medicinal Chemistry, 15 (14). pp. 4741-4752.

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Abstract

The benzo[c]phenanthridines (BCPs) are a group of compounds that are believed to express their antitumor activity through the inhibition of topoisomerase I. The enzyme is crucial to cell cycle division and progression, and regulates the equilibrium between relaxed and supercoiled DNA that occurs during DNA replication. Over the years, we have prepared a number of BCPs and employed a number of biophysical techniques to explore their mechanism of action and improve their activity against this particular enzyme. The naturally occurring alkaloid fagaronine 1 and the synthetic compound ethoxidine 3 are two of the most active compounds, although their inhibitory mechanisms are different, being a poison and suppressor, respectively. We have modified the approach of steered molecular dynamics to create a torque on the intercalator to comprehensively sample the DNA binding site, and using topoisomerase I crystal structures, have proposed a model to explain the different mechanisms of action for these two BCP compounds.