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

R.L. Clark, F.M. Deane, N.G. Anthony, B.F. Johnston, F.O. McCarthy, S.P. Mackay

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)4741-4752
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number14
DOIs
Publication statusPublished - 15 Jul 2007

Fingerprint

Phenanthridines
Type I DNA Topoisomerase
Molecular Dynamics Simulation
Molecular dynamics
Intercalating Agents
Superhelical DNA
Poisons
DNA
Torque
Enzymes
DNA Replication
Alkaloids
Cell Cycle
Crystal structure
Binding Sites
Cells
ethoxidine
fagaronine

Keywords

  • benzo[c]phenanthridine
  • topoisomerase
  • intercalator
  • molecular dynamics

Cite this

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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.",
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Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics. / Clark, R.L.; Deane, F.M.; Anthony, N.G.; Johnston, B.F.; McCarthy, F.O.; Mackay, S.P.

In: Bioorganic and Medicinal Chemistry , Vol. 15, No. 14, 15.07.2007, p. 4741-4752.

Research output: Contribution to journalArticle

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AU - Clark, R.L.

AU - Deane, F.M.

AU - Anthony, N.G.

AU - Johnston, B.F.

AU - McCarthy, F.O.

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AB - 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.

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