Nucleic Acids Res. 2000 Feb 1;28(3):728-35.
Gavathiotis E, Sharman GJ, Searle MS.
The majority of small molecules that bind in the minor groove of duplex DNA, including distamycin and Hoechst 33258, have a marked preference for AT rich sequences.
Recently it has been suggested that sequence specificity may be dominated by ability to select binding sites on the basis of groove width, allowing optimum van der Waal’s complementarity and hydrophobic surface burial, rather than specific hydrogen bonding interactions with the groove floor
Título: Theoretical study of molecular recognition by Hoechst 33258 derivatives
Autor(es): Kakkar, R; Suruchi; Grover, R
Fonte: JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS Volume: 23 Edição: 1 Páginas: 37-47 Publicado: AUG
2005
Número de citações: 6 (de todas as bases de dados)
The factors responsible for the binding of Hoechst 33258 with DNA residues have been investigated in this work using the AMI method. First and foremost, it is found that, although all crystal structure determinations indicate a preference for binding at AT rich sites, the hydrogen bond strength is actually greater for complexes with cytosine and guanine. From this, it has been inferred that other factors such as electrostatic, van der Waals interactions and nonbonded contacts with the walls of the minor groove have a strong role to play in the binding process. The hydrogen bond is found to be stronger for complexation with the thymine O-2 than with the adenine N-3, in line with experimental observations. Combined QM/MM studies on the drug complexed with the Dickerson-Drew dodecamer reveal that binding induces structural changes in both the ligand as well as DNA. Electron donating substituents at the para position in the phenyl ring of Hoechst 3:3258 lead to stronger binding with DNA. A correlation with the octanol/water partition coefficients points to the importance of hydrophobic and electrostatic interactions.
Título: A molecular thermodynamic view of DNA-drug interactions: a case study of 25 minor-groove binders
Autor(es): Shaikh, SA; Ahmed, SR; Jayaram, B
Fonte: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Volume: 429 Edição: 1 Páginas: 81-99 DOI: 10.1016/j.abb.2004.05.019 Publicado: SEP 1
2004
Número de citações: 52 (de todas as bases de dados)
Developing a molecular view of the thermodynamics of DNA recognition is essential to the design of ligands for regulating gene expression. In a first comprehensive attempt at sketching an atlas of DNA–drug energetics, we present here a detailed thermodynamic view of minor-groove recognition by small molecules via a computational study on 25 DNA–drug complexes. The studies are configured in the MMGBSA (Molecular Mechanics-Generalized Born-Solvent Accessibility) framework at the current state of the art and facilitate a structure–energy component correlation. Analyses were conducted on both energy minimized structures of DNA–drug complexes and molecular dynamics trajectories developed for the purpose of this study. While highlighting the favorable role of packing, shape complementarity, and van der Waals and hydrophobic interactions of the drugs in the minor groove in conformity with experiment, the studies reveal an interesting annihilation of favorable electrostatics by desolvation. Structural modifications attempted on the ligands point to the requisite physico-chemical factors for obtaining improved binding energies. Hydrogen bonds predicted to be important for specificity based on structural considerations do not always turn out to be significant to binding in post facto analyses of molecular dynamics trajectories, which treat thermal averaging, solvent, and counterion effects rigorously. The strength of the hydrogen bonds retained between the DNA and drug during the molecular dynamics simulations is ∼1 kcal/mol. Overall, the study reveals the compensatory nature of the diverse binding free energy components, possible threshold limits for some of these properties, and the availability of a computationally viable free energy methodology which could be of value in drug-design endeavors.
Título: DNA-binding of drugs used in medicinal therapies
Autor(es): Bischoff, G; Hoffmann, S
Fonte: CURRENT MEDICINAL CHEMISTRY Volume: 9 Edição: 3 Páginas: 321-348 Publicado: FEB
2002
Número de citações: 42 (de todas as bases de dados)
The interactions of various low-molecular weight substances with DNA are naturally relevant mechanisms in the cellular cycle and so also used in medicinal treatment. Depending on the particular drug structure, DNA-binding modes like groove-binding, intercalating and/or stacking, give rise to supramolecular assemblies of the polynucleotides, as well as influence the DNA-protein binding.
In this review, we compare the underlying molecular structures, including general aspects of DNA sequences, with the benefit in medicinal treatment. While so far interest in this field had mainly been devoted to isolated nucleic acid/drug interactions, the present paper will focus on drug efficiencies generating and influencing supramolecular organizations and their complex sequence-dependent structure-activity codes. In particular, the attention will be directed to stereoelectronic relationships. Spatial enantioselective properties are discussed in details. As examples, the drug self-assemblies, as well as the influence of drugs on supramolecular DNA formations are described. A hypothetical connection between drug-influenced DNA-toroids and the formation of micronuclei in tissues will be interpreted.
Título: Recent developments in sequence selective minor groove DNA effectors
Autor(es): Reddy, BSP; Sharma, SK; Lown, JW
Fonte: CURRENT MEDICINAL CHEMISTRY Volume: 8 Edição: 5 Páginas: 475-508 Publicado: APR
2001
Número de citações: 86 (de todas as bases de dados)
Título: A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity
Autor(es): Mann, J; Baron, A; Opoku-Boahen, Y; et al.
Fonte: JOURNAL OF MEDICINAL CHEMISTRY Volume: 44 Edição: 2 Páginas: 138-144 DOI: 10.1021/jm000297b Publicado: JAN 18
2001
Número de citações: 130 (de todas as bases de dados)
Título: DNA minor-groove recognition by small molecules
Autor(es): Neidle, S
Fonte: NATURAL PRODUCT REPORTS Volume: 18 Edição: 3 Páginas: 291-309 DOI: 10.1039/a705982e Publicado:
2001
Número de citações: 224 (de todas as bases de dados)
Título: Structural studies of atom-specific anticancer drugs acting on DNA
Autor(es): Yang, XL; Wang, AHJ
Fonte: PHARMACOLOGY & THERAPEUTICS Volume: 83 Edição: 3 Páginas: 181-215 DOI: 10.1016/S0163-7258(99)00020-0 Publicado: SEP
1999
Número de citações: 149 (de todas as bases de dados)
Rational recognition of nucleic acid sequences
Hirokazu Iida, Guofeng Jia, J William Lown E-mail the corresponding author
Current Opinion in Biotechnology
Volume 10, Issue 1, 1 February
1999, Pages 29–33
Factors contributing to the molecular recognition of DNA binders
Although the structures of Hoechst 33258 and netropsin are ostensibly quite dissimilar, examination of the molecular recognition surface components of the two ligands directed towards the DNA minor-groove receptor reveals significant similarities.
Based on not only X-ray analysis but also NMR and biological techniques of assessing DNA–minor-groove-binder interactions, progress has been made in understanding some of the factors contributing to the molecular recognition processes:
- firstly, the ability of certain hydrogen bond accepting heterocylic moieties towards specific basepair recognition;
- secondly, the influence of ligand cationic charge in sequence-selective binding;
- thirdly, certain van der Waals, contacts in 3′-terminal basepair recognition;
- and finally, electrostatic interactions between the polyanionic DNA and the cationic compounds, which are sequence dependent
Titulo:
Antihelicase Action of DNA-Binding Anticancer Agents: Relationship to Guanosine-Cytidine Intercalator Binding
An additional interesting correlation is the antihelicase action of DNA-intercalating antibiotics and their DNA-binding preference for G-C base pair sites.
The G-C base pair binding preference of the intercalating antibiotics may result from evolutionary selection because of the higher G-C binding stability, compared with A-T
binding stability. The combination of the higher base pair stability at G-C regions and increased duplex DNA stability induced by intercalating antibiotic yields a total additive stability of the intercalator-G-C base pair complex that resists helicase action.
DNA-intercalating antibiotics stabilize duplex DNA and increase
the energy required to separate paired DNA strands (i.e.,
DNA melting) (17). The DNA-intercalating antibiotics daunorubicin
(10), actinomycin D (11), elsamicin (12), and echinomycin
(13) bind preferentially at G-C base pairs of duplex
DNA, as do most natural intercalating antibiotics. G-C base
pairs in duplex DNA have much greater electronic complementarity
than do the A-T base pairs and are the most stable of
the hydrogen-bonded base pairs, as seen in DNA melting. A
reasonable assumption is that the maximal DNA helicase catalytic
power is used to separate G-C base pairs. The combination
ofthe high G-C base pair stability and the increased duplex
DNA stability produced by an intercalated antibiotic at a G-C
site increases the overall duplex DNA stability at the intercalator-
G-C locus. This supernormal duplex DNA stability at the
intercalator-G-C locus may exceed the catalytic power exerted
by helicases to affect duplex DNA strand separation and may
thus slow or stop helicase action. The factor of G-C base pair
stability may have helped to determine the evolutionary selection
of intercalating antibiotics for G-C-binding specificity.
Título:CORRELATION OF THE BASE SPECIFICITY OF DNA - INTERCALATING
LIGANDS WITH THEIR PHYSICO-CHEMICAL PROPERTIES
From analysis of eqs. l-6 a number of conclusions
may be drawn concerning the affinity and specificity
of heterocyclic ligands for DNA. The relative hydro-
phobicities of the ligands correlate neither with the
affinity for DNA nor with the base specificity (eqs. 2
and 5). At physiological pH the ligands are present
almost exclusively in the ionised form in which form
they interact with DNA. One would therefore expect
that electronic parameters would be more important
in determining binding. Eq. 1 shows some correlation
between affinity for DNA and charge transfer inter-
action. This correlation is improved slightly by adding
the hydrophobicity parameter (eq. 3). This suggests
that binding affinity for DNA depends on-a number
of different parameters, electronic, hydrophobic and
also possibly steric. Base specificity on the other hand
appears to depend almost exclusively on electronic factors. This is shown by the very good linear correla-
tion between Miiller’s (Y value and the relative charge
transfer affinity constant KGMP (eq. 4) which is not
significantly altered by the addition of the hydro-
phobicity parameter (eq. 6).
Thus we have shown that base specificity in these
ligands is related to their electronic characteristics.
These are in turn related to chemical structure and
IV-methylation increases both base specificity and
relative charge transfer affinity. The precise effect of
slight variations of chemical structure on the electronic 1
characteristics of the molecule and also the importance
of steric parameters in binding affinity and base
specificity needs to be further investigated.
Título:
Cancer drug resistance: an evolving paradigm Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research
DOI: 10.1093/NAR/28.3.728 -
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