Molecular modeling of the interaction of anthracenyl-amino acid topoisomerase inhibitors with the DNA sequence d(CGTACG).

2.50
Hdl Handle:
http://hdl.handle.net/10541/95844
Title:
Molecular modeling of the interaction of anthracenyl-amino acid topoisomerase inhibitors with the DNA sequence d(CGTACG).
Authors:
Cummings, Jeffrey; Hadfield, John A; Meikle, I; McGown, Alan T; Smyth, J F
Abstract:
Anthracenyl-amino acid and dipeptide conjugates represent new classes of topoisomerase (topo) inhibitors. To investigate the structural basis for their different selectivity against topo I and II and varying potency, the binding of six compounds to d(CGTACG) was studied by molecular modeling. Modeling data were in good agreement with physical data showing that five compounds intercalated DNA with the anthraquinone chromophore orientated in parallel to the long dimension of the d(CpG) base pairs and the amino acid placed in the minor groove. Differences in binding modes emerged which correlated to different biological properties. The amino acid chain of the topo I inhibitor (NU/ICRF 600, gly-phe) extended significantly out from the helical axis horizontal. The amino acid side chains of two topo II inhibitors (NU/ICRF 510, arginine and NU/ ICRF 512, methionine) were inserted into the minor groove, whereas the C-terminal groups (hydrazide) of two potent topo II inhibitors (NU/ICRF 500 and 506, serine) were placed into the minor groove while the amino acid side chains pointed away from the minor groove. These data provide structural information which may prove valuable in rational design of second generation analogs.
Affiliation:
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
Citation:
Molecular modeling of the interaction of anthracenyl-amino acid topoisomerase inhibitors with the DNA sequence d(CGTACG). 1996, 7 (6):636-41 Anticancer Drugs
Journal:
Anti-Cancer Drugs
Issue Date:
Aug-1996
URI:
http://hdl.handle.net/10541/95844
PubMed ID:
8913431
Type:
Article
Language:
en
ISSN:
0959-4973
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorCummings, Jeffreyen
dc.contributor.authorHadfield, John Aen
dc.contributor.authorMeikle, Ien
dc.contributor.authorMcGown, Alan Ten
dc.contributor.authorSmyth, J Fen
dc.date.accessioned2010-04-07T10:37:29Z-
dc.date.available2010-04-07T10:37:29Z-
dc.date.issued1996-08-
dc.identifier.citationMolecular modeling of the interaction of anthracenyl-amino acid topoisomerase inhibitors with the DNA sequence d(CGTACG). 1996, 7 (6):636-41 Anticancer Drugsen
dc.identifier.issn0959-4973-
dc.identifier.pmid8913431-
dc.identifier.urihttp://hdl.handle.net/10541/95844-
dc.description.abstractAnthracenyl-amino acid and dipeptide conjugates represent new classes of topoisomerase (topo) inhibitors. To investigate the structural basis for their different selectivity against topo I and II and varying potency, the binding of six compounds to d(CGTACG) was studied by molecular modeling. Modeling data were in good agreement with physical data showing that five compounds intercalated DNA with the anthraquinone chromophore orientated in parallel to the long dimension of the d(CpG) base pairs and the amino acid placed in the minor groove. Differences in binding modes emerged which correlated to different biological properties. The amino acid chain of the topo I inhibitor (NU/ICRF 600, gly-phe) extended significantly out from the helical axis horizontal. The amino acid side chains of two topo II inhibitors (NU/ICRF 510, arginine and NU/ ICRF 512, methionine) were inserted into the minor groove, whereas the C-terminal groups (hydrazide) of two potent topo II inhibitors (NU/ICRF 500 and 506, serine) were placed into the minor groove while the amino acid side chains pointed away from the minor groove. These data provide structural information which may prove valuable in rational design of second generation analogs.en
dc.language.isoenen
dc.subject.meshAmino Acids-
dc.subject.meshAnthraquinones-
dc.subject.meshArginine-
dc.subject.meshDNA-
dc.subject.meshDNA Topoisomerases, Type I-
dc.subject.meshDNA Topoisomerases, Type II-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshModels, Molecular-
dc.subject.meshSerine-
dc.subject.meshTyrosine-
dc.titleMolecular modeling of the interaction of anthracenyl-amino acid topoisomerase inhibitors with the DNA sequence d(CGTACG).en
dc.typeArticleen
dc.contributor.departmentImperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, UK.en
dc.identifier.journalAnti-Cancer Drugsen

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