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Special Issue "G-Quadruplex Ligands and Cancer"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 15 March 2019

Special Issue Editor

Guest Editor
Prof. Danzhou Yang

Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, Purdue Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907, USA
Website | E-Mail
Interests: DNA structures and functions; G-quadruplexes; anticancer drugs; NMR; ligand interactions

Special Issue Information

Dear Colleagues,

G-quadruplexes are four-stranded nucleic acid secondary structures, which form in guanine-rich DNA and RNA sequences. Once a laboratory curiosity, these non-canonical structures are now known to form readily under physiological conditions in regions of biological significance, such as human telomeres, oncogene promoter regions, replication initiation sites, and 5’ and 3’-untranslated (UTR) regions. Many G-quadruplex forming sequences are found to be associated with cancer, thus, these non-canonical nucleic acid structures are considered to be attractive molecular targets for cancer therapeutics with novel mechanisms of action. In recent years, G-quadruplexes have received elevated research interest, and G-quadruplex interactive ligands have been identified to exhibit antiproliferative and chemosensitizing effects against tumor models both in vitro and in vivo. Notably, quarfloxin, a G-quadruplex-interactive fluoroquinoline derivative, reached phase II clinical trials for the treatment of carcinoid/neuroendocrine tumors. While significant advances have been made towards targeting G-quadruplex structures, many questions and challenges on the subject remain to be addressed. This Special Issue aims to provide opportunity to share new findings and recent advances on G-quadruplex targeted small-molecules toward the development of new anticancer drugs.

Prof. Danzhou Yang
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access bimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • G-quadruplexes nucleic acid secondary structures
  • molecular targets for cancer therapeutics
  • G-quadruplex-targeted ligands
  • anticancer and chemosensitizing effects

Published Papers (9 papers)

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Research

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Open AccessArticle Synthesis and Telomeric G-Quadruplex-Stabilizing Ability of Macrocyclic Hexaoxazoles Bearing Three Side Chains
Molecules 2019, 24(2), 263; https://doi.org/10.3390/molecules24020263
Received: 13 December 2018 / Revised: 4 January 2019 / Accepted: 10 January 2019 / Published: 11 January 2019
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Abstract
G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore “sequence-dependent” selective G4-stabilizing agents are required as tools to investigate and modulate these functions. Here, we describe the synthesis of a
[...] Read more.
G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore “sequence-dependent” selective G4-stabilizing agents are required as tools to investigate and modulate these functions. Here, we describe the synthesis of a new series of macrocyclic hexaoxazole-type G4 ligand (6OTD) bearing three side chains. One of these ligands, 5b, stabilizes telomeric G4 preferentially over the G4-forming DNA sequences of c-kit and K-ras, due to the interaction of its piperazinylalkyl side chain with the groove of telomeric G4. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle Binding of Small Molecules to G-quadruplex DNA in Cells Revealed by Fluorescence Lifetime Imaging Microscopy of o-BMVC Foci
Received: 15 November 2018 / Revised: 12 December 2018 / Accepted: 19 December 2018 / Published: 21 December 2018
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Abstract
G-quadruplex (G4) structures have recently received increasing attention as a potential target for cancer research. We used time-gated fluorescence lifetime imaging microscopy (FLIM) with a G4 fluorescent probe, 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (o-BMVC), to measure the number of o-BMVC foci, which
[...] Read more.
G-quadruplex (G4) structures have recently received increasing attention as a potential target for cancer research. We used time-gated fluorescence lifetime imaging microscopy (FLIM) with a G4 fluorescent probe, 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (o-BMVC), to measure the number of o-BMVC foci, which may represent G4 foci, in cells as a common signature to distinguish cancer cells from normal cells. Here, the decrease in the number of o-BMVC foci in the pretreatment of cancer cells with TMPyP4, BRACO-19 and BMVC4 suggested that they directly bind to G4s in cells. In contrast, the increase in the number of o-BMVC foci in the pretreatment of cells with PDS and Hoechst 33258 (H33258) suggested that they do not inhabit the binding site of o-BMVC to G4s in cells. After the H33258 was removed, the gradual decrease of H33258-induced G4 foci may be due to DNA repair. The purpose of this work is to introduce o-BMVC foci as an indicator not only to verify the direct binding of potential G4 ligands to G4 structures but also to examine the possible effect of some DNA binding ligands on DNA integrity by monitoring the number of G4 foci in cells. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle Design and Properties of Ligand-Conjugated Guanine Oligonucleotides for Recovery of Mutated G-Quadruplexes
Molecules 2018, 23(12), 3228; https://doi.org/10.3390/molecules23123228
Received: 14 November 2018 / Revised: 27 November 2018 / Accepted: 5 December 2018 / Published: 6 December 2018
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Abstract
The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a
[...] Read more.
The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a ligand-containing guanine tract that replaces the mutated G4 guanine tract at the promoter of the vascular endothelial growth factor (VEGF) gene. A ligand moiety consisting of three types of polyaromatic hydrocarbons, pyrene, anthracene, and perylene, was attached to either the 3′ or 5′ end of the guanine tract. Each of the ligand-conjugated guanine tracts, with the exception of anthracene derivatives, combined with other intact guanine tracts to form an intermolecular G4 on the mutated VEGF promoter. This intermolecular G4, exhibiting parallel topology and high thermal stability, enabled VEGF G4 formation to be recovered from the mutated sequence. Stability of the intramolecular G4 increased with the size of the conjugated ligand. However, suppression of intermolecular G4 replication was uniquely dependent on whether the ligand was attached to the 3′ or 5′ end of the guanine tract. These results indicate that binding to either the top or bottom guanine quartet affects unfolding kinetics due to polarization in DNA polymerase processivity. Our findings provide a novel strategy for recovering G4 formation in case of damage, and fine-tuning processes such as replication and transcription. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle Binding Study of the Fluorescent Carbazole Derivative with Human Telomeric G-Quadruplexes
Molecules 2018, 23(12), 3154; https://doi.org/10.3390/molecules23123154
Received: 4 November 2018 / Revised: 28 November 2018 / Accepted: 29 November 2018 / Published: 30 November 2018
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Abstract
The carbazole ligand 3 was synthesized, characterized and its binding interactions with human telomeric (22HT) G-quadruplex DNA in Na+ and K+-containing buffer were investigated by ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence, circular dichroism (CD) spectroscopy, and DNA melting. The results showed that
[...] Read more.
The carbazole ligand 3 was synthesized, characterized and its binding interactions with human telomeric (22HT) G-quadruplex DNA in Na+ and K+-containing buffer were investigated by ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence, circular dichroism (CD) spectroscopy, and DNA melting. The results showed that the studied carbazole ligand interacted and stabilized the intramolecular G-quadruplexes formed by the telomeric sequence in the presence of sodium and potassium ions. In the UV-Vis titration experiments a two-step complex formation between ligand and G-quadruplex was observed. Very low fluorescence intensity of the carbazole derivative in Tris HCl buffer in the presence of the NaCl or KCl increased significantly after addition of the 22HT G4 DNA. Binding stoichiometry of the ligand/G-quadruplex was investigated with absorbance-based Job plots. Carbazole ligand binds 22HT with about 2:1 stoichiometry in the presence of sodium and potassium ions. The binding mode appeared to be end-stacking with comparable binding constants of ~105 M−1 as determined from UV-Vis and fluorescence titrations data. The carbazole ligand is able to induce formation of G4 structure of 22HT in the absence of salt, which was proved by CD spectroscopy and melting studies. The derivative of carbazole 3 shows significantly higher cytotoxicity against breast cancer cells then for non-tumorigenic breast epithelial cells. The cytotoxic activity of ligand seems to be not associated with telomerase inhibition. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessFeature PaperArticle Molecular Recognition of Parallel G-quadruplex [d-(TTGGGGT)]4 Containing Tetrahymena Telomeric DNA Sequence by Anticancer Drug Daunomycin: NMR-Based Structure and Thermal Stability
Molecules 2018, 23(9), 2266; https://doi.org/10.3390/molecules23092266
Received: 10 August 2018 / Revised: 27 August 2018 / Accepted: 4 September 2018 / Published: 5 September 2018
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Abstract
The anticancer drug daunomycin exerts its influence by multiple strategies of action to interfere with gene functioning. Besides inhibiting DNA/RNA synthesis and topoisomerase-II, it affects the functional pathway of telomere maintenance by the telomerase enzyme. We present evidence of the binding of daunomycin
[...] Read more.
The anticancer drug daunomycin exerts its influence by multiple strategies of action to interfere with gene functioning. Besides inhibiting DNA/RNA synthesis and topoisomerase-II, it affects the functional pathway of telomere maintenance by the telomerase enzyme. We present evidence of the binding of daunomycin to parallel-stranded tetramolecular [d-(TTGGGGT)]4 guanine (G)-quadruplex DNA comprising telomeric DNA from Tetrahymena thermophilia by surface plasmon resonance and Diffusion Ordered SpectroscopY (DOSY). Circular Dichroism (CD) spectra show the disruption of daunomycin dimers, suggesting the end-stacking and groove-binding of the daunomycin monomer. Proton and phosphorus-31 Nuclear Magnetic Resonance (NMR) spectroscopy show a sequence-specific interaction and a clear proof of absence of intercalation of the daunomycin chromophore between base quartets or stacking between G-quadruplexes. Restrained molecular dynamics simulations using observed short interproton distance contacts depict interaction at the molecular level. The interactions involving ring A and daunosamine protons, the stacking of an aromatic ring of daunomycin with a terminal G6 quartet by displacing the T7 base, and external groove-binding close to the T1–T2 bases lead to the thermal stabilization of 15 °C, which is likely to inhibit the association of telomerase with telomeres. The findings have implications in the structure-based designing of anthracycline drugs as potent telomerase inhibitors. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle HnRNPA1 Specifically Recognizes the Base of Nucleotide at the Loop of RNA G-Quadruplex
Molecules 2018, 23(1), 237; https://doi.org/10.3390/molecules23010237
Received: 13 December 2017 / Revised: 5 January 2018 / Accepted: 16 January 2018 / Published: 22 January 2018
Cited by 1 | PDF Full-text (910 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Human telomere RNA performs various cellular functions, such as telomere length regulation, heterochromatin formation, and end protection. We recently demonstrated that the loops in the RNA G-quadruplex are important in the interaction of telomere RNA with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Here, we
[...] Read more.
Human telomere RNA performs various cellular functions, such as telomere length regulation, heterochromatin formation, and end protection. We recently demonstrated that the loops in the RNA G-quadruplex are important in the interaction of telomere RNA with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Here, we report on a detailed analysis of hnRNPA1 binding to telomere RNA G-quadruplexes with a group of loop variants using an electrophoretic mobility shift assay (EMSA) and circular dichroism (CD) spectroscopy. We found that the hnRNPA1 binds to RNA G-quadruplexes with the 2’-O-methyl and DNA loops, but fails to bind with the abasic RNA and DNA loops. These results suggested that hnRNPA1 binds to the loop of the RNA G-quadruplex by recognizing the base of the loop’s nucleotides. The observation provides the first evidence that the base of the loop’s nucleotides is a key factor for hnRNPA1 specifically recognizing the RNA G-quadruplex. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle Design, Synthesis and Biological Evaluation of New Substituted Diquinolinyl-Pyridine Ligands as Anticancer Agents by Targeting G-Quadruplex
Received: 8 December 2017 / Revised: 20 December 2017 / Accepted: 29 December 2017 / Published: 30 December 2017
Cited by 2 | PDF Full-text (2846 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore
[...] Read more.
G-quadruplexes (G4) are stacked non-canonical nucleic acid structures found in specific G-rich DNA or RNA sequences in the human genome. G4 structures are liable for various biological functions; transcription, translation, cell aging as well as diseases such as cancer. These structures are therefore considered as important targets for the development of anticancer agents. Small organic heterocyclic molecules are well known to target and stabilize G4 structures. In this article, we have designed and synthesized 2,6-di-(4-carbamoyl-2-quinolyl)pyridine derivatives and their ability to stabilize G4-structures have been determined through the FRET melting assay. It has been established that these ligands are selective for G4 over duplexes and show a preference for the parallel conformation. Next, telomerase inhibition ability has been assessed using three cell lines (K562, MyLa and MV-4-11) and telomerase activity is no longer detected at 0.1 μM concentration for the most potent ligand 1c. The most promising G4 ligands were also tested for antiproliferative activity against the two human myeloid leukaemia cell lines, HL60 and K562. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Open AccessArticle Investigation of ‘Head-to-Tail’-Connected Oligoaryl N,O-Ligands as Recognition Motifs for Cancer-Relevant G-Quadruplexes
Molecules 2017, 22(12), 2160; https://doi.org/10.3390/molecules22122160
Received: 27 October 2017 / Revised: 22 November 2017 / Accepted: 2 December 2017 / Published: 6 December 2017
Cited by 2 | PDF Full-text (2287 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Oligomeric compounds, constituted of consecutive N,O-heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C–H activation of the
[...] Read more.
Oligomeric compounds, constituted of consecutive N,O-heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C–H activation of the formed oxazoles and their subsequent C–C cross-coupling to 2-bromopyridines in order to assemble a library of variable-length, ‘head-to-tail’-connected, pyridyl-oxazole ligands. Through investigation of the interaction of the three longer ligands (5-mer, 6-mer, 7-mer) with cancer-relevant G-quadruplex structures (human telomeric/22AG and c-Myc oncogene promoter/Myc2345-Pu22), the asymmetric pyridyl-oxazole motif has been demonstrated to be a prominent recognition element for G-quadruplexes. Fluorescence titrations reveal excellent binding affinities of the 7-mer and 6-mer for a Na+-induced antiparallel 22AG G-quadruplex (KD = 0.6 × 10−7 M−1 and 0.8 × 10−7 M−1, respectively), and satisfactory (albeit lower) affinities for the 22AG/K+ and Myc2345-Pu22/K+ G-quadruplexes. All ligands tested exhibit substantial selectivity for G-quadruplex versus duplex (ds26) DNA, as evidenced by competitive Förster resonance energy transfer (FRET) melting assays. Additionally, the 7-mer and 6-mer are capable of promoting a sharp morphology transition of 22AG/K+ G-quadruplex. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Review

Jump to: Research

Open AccessReview Natural Alkaloids and Heterocycles as G-Quadruplex Ligands and Potential Anticancer Agents
Molecules 2018, 23(2), 493; https://doi.org/10.3390/molecules23020493
Received: 30 December 2017 / Revised: 4 February 2018 / Accepted: 20 February 2018 / Published: 23 February 2018
Cited by 2 | PDF Full-text (1793 KB) | HTML Full-text | XML Full-text
Abstract
G-quadruplexes are four-stranded nucleic acid secondary structures that are formed in guanine-rich sequences. G-quadruplexes are widely distributed in functional regions of the human genome and transcriptome, such as human telomeres, oncogene promoter regions, replication initiation sites, and untranslated regions. Many G-quadruplex-forming sequences are
[...] Read more.
G-quadruplexes are four-stranded nucleic acid secondary structures that are formed in guanine-rich sequences. G-quadruplexes are widely distributed in functional regions of the human genome and transcriptome, such as human telomeres, oncogene promoter regions, replication initiation sites, and untranslated regions. Many G-quadruplex-forming sequences are found to be associated with cancer, and thus, these non-canonical nucleic acid structures are considered to be attractive molecular targets for cancer therapeutics with novel mechanisms of action. In this mini review, we summarize recent advances made by our lab in the study of G-quadruplex-targeted natural alkaloids and their derivatives toward the development of potential anticancer agents. Full article
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Design and property of ligand-conjugated guanine tract for recovery of mutated G-quadruplexes
Authors: Naoki Sugimoto and Takahashi Shuntaro; [email protected] (N.S.) [email protected] (T.S.)
Abstract: Because the formation of G4 represses the expression of some cancer-related genes, the mutation in a G4 sequence might affect G4 formation and induce cancer progression. In this study, we will report about the development of an oligonucleotide consisting of a ligand-modified guanine tract that replaces the mutated guanine tract and forms stable intermolecular G4s with the other intact guanine tracts. We will show the effect of ligand molecule and the structure of the modified guanine tract on the recovery of the formation of the mutated G4 derived from the human vascular endothelial growth factor (VEGF).

Title: G-Quadruplex targeting ligands: A hope and a new horizon in Cancer therapeutics
Anthors: Nilanjan Banerjee, Suman Panda and Subhrangsu Chatterjee*
Affiliation: Department of Biophysics, Bose Institute, P-1/12 CIT Road, Scheme VIIM, Kankurgachi, Kolkata, Pin-700054, India
Abstract: G-quadruplex, a unique secondary structure in nucleic acids found throughout human genome elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, G-quadruplex structure regulates transcription, translation, splicing, telomere stability etc. Changes in its structure and stability lead to differential expression of oncogenes causing cancer. Thus, targeting quadruplex structures with small molecules/ other biologics has shown elevated research interest. Covering previous reports, in this review we try to enlighten the facts on the structural diversity in G-quadruplex ligands aiming to provide newer insights to design first-in-class drugs for the next generation cancer treatment.

Title: Synthetic ligands targeted to selected G-quadruplex as potential anticancer drugs
Authors: Sefan Asamitsu, Shunsuke Obata, Zutao Yu, Toshikazu Bando and Hiroshi Sugiyama*
Affiliation: Department of Chemistry, Graduate School of Science Kyoto University, Kitashirakawa-Oiwakecho, Sakyo, Kyoto, 606-8502, Japan
Abstract: A G-quadruplex (G4) is a well-known nucleic acid secondary structure adopted by guanine-rich sequences and is deeply relevant to various pharmacological/biological events and cancers. Therefore, G4 ligands have attracted great attention as potential anticancer therapies or in molecular probe applications. To date, a large variety of DNA/RNA G4 ligands has been developed by a number of laboratories. In this review, we would like to address the recent researches on synthetic G4 ligands that allow targeting of selected G4s toward the discovery of highly effective anticancer drugs.

Title: Synthesis of macrocyclic hexaoxoazoles with tri-substituted side chains and their stabilization ability of telomeric G-quadruplex
Authors: Kazuo Nagasawa, Yue Ma and Keisuke Iida
Abstract:G-quadruplexes (G4s), forms in guanine rich regions, have been recognized to involve in variety of significant biological functions, thus selective stabilization agents for specific G-quadruplex are required for regulation of the corresponding functions. In this article, we will describe about our recent efforts for developing new series of macrocyclic hexaoxazole type G4 ligands. These ligands enable us to stabilize telomeric G4 preferentially by introducing groove recognition moiety of side chain in the macrocyclic core structure.

Title: Binding of BRACO19 to human Telomeric G-Quadruplexes Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent
Authors: Babitha Machireddy, Holli-Joi Sullivan and Chun Wu*
Affiliation: College of Science and Mathematics, Rowan University, Glassboro, NJ, 08028 USA
To whom correspondence should be addressed: Abstract: BRACO19, a potent human telomeric DNA G-quadruplex binder, has shown  high efficacy to inhibit various tumor cell growth, however its low (62-fold) preferential binding affinity towards DNA G-quadruplex over  DNA duplex limits its clinic applications as a cancer drug. High  resolution structures of BRACO19 in complex with neither  single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are  available yet. Consequently, the binding nature of BRACO19 to these  DNA forms remain elusive. In this study, the binding pathway of BRACO19 is characterized by a total of 26 µs molecular dynamics  binding simulations with a free ligand (BRACO19) to a DNA duplex and  three different topological folds of the human telomeric DNA  G-quadruplex (parallel, antiparallel and hybrid).

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