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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. June 2006, Volume 5, Number 6, 320-330 |
Molecular Modeling of the Interaction of Some Phenoxazone-Antitumoral Drugs with DNA
Cezar Bendic and Elena Volanschi
Internet Electron. J. Mol. Des. 2006, 5, 320-330
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Abstract:
The study of the interactions between double stranded
deoxyribonucleic acid (DNA) and different binding agents is of
major importance in the understanding of biochemical processes.
Many aspects concerning the structural factors determining one
type or another of the drug-DNA interaction mechanism
(intercalation or minor groove binding) are not yet elucidated,
especially in aqueous solutions. The objective of the present paper
is to evaluate the contribution of the different structural factors that
determine the main binding mechanism, intercalation or minor
grove binding, for several iminoquinone (phenoxazinone) drugs,
using molecular modeling and quantum-chemical calculations. The
models of the drug-nucleic acid complexes were built by manual
docking followed by molecular mechanics optimization with
implicit solvent effect using OPLS force field. In order to identify
and analyze intermolecular interactions for the drug-DNA
complexes, the SHB_interactions program, based on EH-calculated
Mulliken overlap populations as a quantitative quantum
chemical criterion, was used. Structural modeling of the solution
drug-DNA complexes and energetic analysis outlines that the
substituents in 1,9 positions are essential for the intercalative
binding mode. The calculated binding energies vary in the same
order as the biological activity questiomycin < 1,9-diacetyl-2-aminophenoxazine-3-one
< protonated 5H-pyrido[3,2-a]phenoxazine-3-one < actinomycin D. Mulliken overlap
populations (OP) analysis allows to identify the classical N-H…O
bonds, as well as C-H…O(N) bonds, which represent 97% from the
OP due to H-bonds. The selectivity and biological activity is
probably due to the H-bonds O5: 2H2 G4 and O3: 2H2 G12
present in all minor groove complexes. Our results show that, in
spite of the drastic approximations implied, the combined use of
molecular mechanics modeling with Mulliken overlap populations
(SHB_interactions program), may provide useful information
about the structural factors controlling the binding mechanism of
the phenoxazinone drugs to dsDNA and outline the specific H-bonds
and other atom-atom interactions which contribute to the
stabilization of drug-DNA complexes. The source code for
SHB_interactions program, written in C, instructions and some
examples are available at
http://gw-chimie.math.unibuc.ro/staff/cbendic/shb/SHB_interactions.html.
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