Nucleic Acids Research, Vol 26, Issue 20 4721-4732, Copyright © 1998 by Oxford University Press
GE Kellogg, JN Scarsdale and FA Fornari Jr
The computer molecular modeling program HINT (Hydropathic INTeractions), an
empirical hydropathic force field function that includes hydrogen bonding,
coulombic and hydrophobic terms, was used to study sequence-selective
doxorubicin binding/intercalation in the 64 unique CAxy, CGxy, TAxy, TGxy
base pair quartet combinations. The CAAT quartet sequence is shown to have
the highest binding score of the 64 combinations. Of the two regularly
alternating polynucleotides, d(CGCGCG)2and d(TATATA)2, the HINT calculated
binding scores reveal doxorubicin binds preferentially to d(TATATA)2.
Although interactions of the chromophore with the DNA base pairs defining
the intercalation site [I-1] [I+1] and the neighboring [I+2] base pair are
predominant, the results obtained with HINT indicate that the base pair
[I+3] contributes significantly to the sequence selectivity of doxorubicin
by providing an additional hydrogen bonding opportunity for the N3'
ammonium of the daunosamine sugar moiety in approximately 25% of the
sequences. This observation, that interactions involving a base pair [I+3]
distal to the intercalation site play a significant role in
stabilizing/destabilizing the intercalation of doxorubicin into the various
DNA sequences, has not been previously reported. In general terms, this
work shows that molecular modeling and careful analysis of molecular
interactions can have a significant role in designing and evaluating
nucleotides and antineoplastic agents.
ARTICLES
Identification and hydropathic characterization of structural features affecting sequence specificity for doxorubicin intercalation into DNA double-stranded polynucleotides
Department of Medicinal Chemistry, School of Pharmacy, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-01. glen.kellogg@vcu.edu
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