title: Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics.
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.
authors.affiliation: Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Clark
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Deane
authors.forename: Nahoum G
authors.initials: NG
authors.lastname: Anthony
authors.forename: Blair F
authors.initials: BF
authors.lastname: Johnston
authors.forename: Florence O
authors.initials: FO
authors.lastname: McCarthy
authors.forename: Simon P
authors.initials: SP
authors.lastname: Mackay
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010617:Phenanthridines / Q000737:chemistry* / Q000494:pharmacology*; D019800:Phenol / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D059004:Topoisomerase I Inhibitors; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D008024:Ligands; D010617:Phenanthridines; D010710:Phosphates; D059004:Topoisomerase I Inhibitors; C404513:ethoxidine; D019800:Phenol; C002066:fagaronine; D014443:Tyrosine; D004247:DNA; D004264:DNA Topoisomerases, Type I