Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations

Lei, Hongxing; Wang, Xiaofeng; Wu, Chun

doi:10.1016/j.jmgm.2012.05.006

Cited by 55 publications

(54 citation statements)

References 52 publications

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“…Water‐mediated interactions between the binder and the backbone have also been analyzed . These studies highlight the importance of the presence of water molecules around the binder because they act as indirect contacts between the drug and the DNA backbone . However, herein we have found that these water bridges are not the only interactions that contribute to the stabilization of the complex; there are also direct contacts between the DNA sugar groups and binder.…”

Section: Introductionmentioning

confidence: 80%

“…[12] These studies highlight the importance of the presenceo fw ater molecules around the binderb ecause they act as indirect contacts between the drug and the DNA backbone. [13][14][15] However,h erein we have found that these water bridges are not the only interactions that con-Molecular recognition between ligands and nucleic acids plays ak ey role in therapeutic activity.S ome molecules interactw ith DNA in an onbonded manner through intercalation or through the DNA grooves. The recognition of minor-groove binders is attributedt oas et of hydrogen-bonding interactions between the bindersa nd the hydrogen-bond-acceptor groups on the groove floor and walls.…”

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confidence: 93%

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The Role of the DNA Backbone in Minor‐Groove Ligand Binding

2017

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Molecular recognition between ligands and nucleic acids plays a key role in therapeutic activity. Some molecules interact with DNA in a nonbonded manner through intercalation or through the DNA grooves. The recognition of minor-groove binders is attributed to a set of hydrogen-bonding interactions between the binders and the hydrogen-bond-acceptor groups on the groove floor and walls. It is commonly considered that interactions with the sugar groups of the DNA backbone are insignificant and do not contribute to the binding affinity or the specificity. However, our group has found that the deoxyribose rings have a central function in the recognition and the intercalation of metal complexes into DNA. Herein, we determined the specific interactions between the binder CGP 40215A and the minor-groove atoms, based on the local properties of electron density. We found that specific interactions between the deoxyribose moiety within the backbone of DNA and the binder are essential for molecular recognition, and they are responsible for one third of the interaction energy.

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Section: Introductionmentioning

confidence: 80%

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confidence: 93%

The Role of the DNA Backbone in Minor‐Groove Ligand Binding

2017

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“…cellular uptake of ang-Ps-DOX DOX inhibits tumor formation and development by intercalating in DNA fragments of tumor cells and hindering DNA transcription and replication. 24 Given this, abundant DOX uptake by the tumor cells is a prerequisite for effective therapy. As shown in Figure 3A, after 1 h incubation, Ang-PS-DOX showed greater accumulation in C6 cells than PS-DOX and DOX solution.…”

Section: In Vitro Cumulative Releasementioning

confidence: 99%

“…Doxorubicin (DOX), an anthracycline ring antibiotic, exerts antitumor activity by interfering with DNA synthesis. 24 It has been extensively used for the treatment of peripheral tumors; however, there is still a huge gap for the clinical application of DOX in brain tumor therapy because of its rapid clearance and poor delivery across the BBB. To solve this problem, DOX has been encapsulated or conjugated with various nanocarriers to utilize the enhanced permeation and retention (EPR) effect of tumor cells.…”

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confidence: 99%

Angiopep-2-conjugated poly(ethylene glycol)-<em>co</em>-poly(ε-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats

Pang

Zhao

et al. 2017

IJN

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The blood–brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX) was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1), which is overexpressed in both blood–brain barrier and glioma cells. The polymersomes (PS) were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX). The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%±0.17% and 95.0%±1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS-DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was significantly prolonged compared with those treated with PS-DOX or a solution of free doxorubicin. These results suggested that Ang-PS-DOX can target glioma cells and enhance chemotherapeutic efficacy.

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“…Small molecules binding genomic DNA have proven to be effective as anticancer, antibiotic and antiviral therapeutic agents, and targeting of DNA to regulate cell functions by modulating gene expression, or by interfering with replication, represents one major goal of modern biomedical research. Many small molecules may interact, or bind, with DNA, and such compounds can be classified by their mechanism of action as groove binders, which sit in the minor groove , intercalators, which are sandwiched between base pairs , alkylators, which chemically react with DNA, resulting in DNA alkylation , and DNA cleavage agents, which have the ability to break DNA chains . The molecules in these different classes have different structures and require opportune parametrization to interact with DNA .…”

Section: State Of the Art In Dna Simulationmentioning

confidence: 99%

Decoding the conformation‐linked functional properties of nucleic acids by the use of computational tools

Iacovelli

Falconi

2015

The FEBS Journal

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DNA and RNA are large and flexible polymers selected by nature to transmit information. The most common DNA three-dimensional structure is represented by the double helix, but this biopolymer is extremely flexible and polymorphic, and can easily change its conformation to adapt to different interactions and purposes. DNA can also adopt singular topologies, giving rise, for instance, to supercoils, formed because of the limited free rotation of the DNA domain flanking a replication or transcription complex. Our understanding of the importance of these unusual or transient structures is growing, as recent studies of DNA topology, supercoiling, knotting and linking have shown that the geometric changes can drive, or strongly influence, the interactions between protein and DNA, so altering its own metabolism. On the other hand, the unique self-recognition properties of DNA, determined by the strict Watson-Crick rules of base pairing, make this material ideal for the creation of self-assembling, predesigned nanostructures. The construction of such structures is one of the main focuses of the thriving area of DNA nanotechnology, where several assembly strategies have been employed to build increasingly complex DNA nanostructures. DNA nanodevices can have direct applications in biomedicine, but also in the materials science field, requiring the immersion of DNA in an environment far from the physiological one. Crucial help in the understanding and planning of natural and artificial nanostructures is given by modern computer simulation techniques, which are able to provide a reliable structural and dynamic description of nucleic acids.

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Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations

Cited by 55 publications

References 52 publications

The Role of the DNA Backbone in Minor‐Groove Ligand Binding

The Role of the DNA Backbone in Minor‐Groove Ligand Binding

Angiopep-2-conjugated poly(ethylene glycol)-<em>co</em>-poly(ε-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats

Decoding the conformation‐linked functional properties of nucleic acids by the use of computational tools

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Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations

Cited by 55 publications

References 52 publications

The Role of the DNA Backbone in Minor‐Groove Ligand Binding

The Role of the DNA Backbone in Minor‐Groove Ligand Binding

Angiopep-2-conjugated poly(ethylene glycol)-<em>co</em>-poly(&epsilon;-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats

Decoding the conformation‐linked functional properties of nucleic acids by the use of computational tools

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Angiopep-2-conjugated poly(ethylene glycol)-<em>co</em>-poly(ε-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats