Journal articles: 'G quadruplex binding ligand'

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Neidle, Stephen. "Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids." Pharmaceuticals 15, no. 1 (December 22, 2021): 7. http://dx.doi.org/10.3390/ph15010007.

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The role of G-quadruplexes in human cancers is increasingly well-defined. Accordingly, G-quadruplexes can be suitable drug targets and many small molecules have been identified to date as G-quadruplex binders, some using computer-based design methods and co-crystal structures. The role of bound water molecules in the crystal structures of G-quadruplex-small molecule complexes has been analyzed in this study, focusing on the water arrangements in several G-quadruplex ligand complexes. One is the complex between the tetrasubstituted naphthalene diimide compound MM41 and a human intramolecular telomeric DNA G-quadruplex, and the others are in substituted acridine bimolecular G-quadruplex complexes. Bridging water molecules form most of the hydrogen-bond contacts between ligands and DNA in the parallel G-quadruplex structures examined here. Clusters of structured water molecules play essential roles in mediating between ligand side chain groups/chromophore core and G-quadruplex. These clusters tend to be conserved between complex and native G-quadruplex structures, suggesting that they more generally serve as platforms for ligand binding, and should be taken into account in docking and in silico studies.

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Oblak, Domen, San Hadži, Črtomir Podlipnik, and Jurij Lah. "Binding-Induced Diversity of a Human Telomeric G-Quadruplex Stability Phase Space." Pharmaceuticals 15, no. 9 (September 15, 2022): 1150. http://dx.doi.org/10.3390/ph15091150.

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The structural polymorphism of G-quadruplex nucleic acids is an important factor in their recognition by proteins and small-molecule ligands. However, it is not clear why the binding of several ligands alters G-quadruplex topology. We addressed this question by following the (un)folding and binding of the human telomeric fragment 5′-(GGGTTA)3GGGT-3′ (22GT) by calorimetry (DSC, ITC) and spectroscopy (CD). A thermodynamic analysis of the obtained data led to a detailed description of the topological phase space of stability (phase diagram) of 22GT and shows how it changes in the presence of a specific bisquinolinium ligand (360A). Various 1:1 and 2:1 ligand–quadruplex complexes were observed. With increasing temperature, the 1:1 complexes transformed into 2:1 complexes, which is attributed to the preferential binding of the ligand to the folding intermediates. Overall, the dissection of the thermodynamic parameters in combination with molecular modelling clarified the driving forces of the topological quadruplex transformations in a wide range of ligand concentrations and temperatures.

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Santos, Tiago, Gilmar F. Salgado, Eurico J. Cabrita, and Carla Cruz. "G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions." Pharmaceuticals 14, no. 8 (August 5, 2021): 769. http://dx.doi.org/10.3390/ph14080769.

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Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be categorized into structure-based methods (circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography), affinity and apparent affinity-based methods (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS)), and high-throughput methods (fluorescence resonance energy transfer (FRET)-melting, G4-fluorescent intercalator displacement assay (G4-FID), affinity chromatography and microarrays. Each method has unique advantages and drawbacks, which makes it essential to select the ideal strategies for the biological question being addressed. The structural- and affinity and apparent affinity-based methods are in several cases complex and/or time-consuming and can be combined with fast and cheap high-throughput approaches to improve the design and development of new potential G4 ligands. In recent years, the joint use of these techniques permitted the discovery of a huge number of G4 ligands investigated for diagnostic and therapeutic purposes. Overall, this review article highlights in detail the most commonly used approaches to characterize the G4/ligand interactions, as well as the applications and types of information that can be obtained from the use of each technique.

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Nowak-Karnowska, Joanna, Agata Głuszyńska, Joanna Kosman, Grażyna Neunert, and Anna Dembska. "Interaction of 9-Methoxyluminarine with Different G-Quadruplex Topologies: Fluorescence and Circular Dichroism Studies." International Journal of Molecular Sciences 22, no. 19 (September 27, 2021): 10399. http://dx.doi.org/10.3390/ijms221910399.

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The interactions of G–quadruplexes of different topologies with highly fluorescent 9-methoxyluminarine ligand 9-MeLM were investigated by fluorescence and circular dichroism spectroscopy. The results showed that 9-methoxyluminarine was able to interact and did not destabilize any investigated molecular targets. The studied compound was selectively quenched by parallel c-MYC G-quadruplex DNA, whereas hybrid and antiparallel G4 topology caused only a negligible decrease in the fluorescence of the ligand. A high decrease of fluorescence of the ligand after binding with c-MYC G-quadruplex suggests that this molecule can be used as a selective probe for parallel G-quadruplexes.

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Hasegawa, Hijiri, Ikkei Sasaki, Kaori Tsukakoshi, Yue Ma, Kazuo Nagasawa, Shusuke Numata, Yuuki Inoue, Yeji Kim, and Kazunori Ikebukuro. "Detection of CpG Methylation in G-Quadruplex Forming Sequences Using G-Quadruplex Ligands." International Journal of Molecular Sciences 22, no. 23 (December 6, 2021): 13159. http://dx.doi.org/10.3390/ijms222313159.

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Genomic DNA methylation is involved in many diseases and is expected to be a specific biomarker for even the pre-symptomatic diagnosis of many diseases. Thus, a rapid and inexpensive detection method is required for disease diagnosis. We have previously reported that cytosine methylation in G-quadruplex (G4)-forming oligonucleotides develops different G4 topologies. In this study, we developed a method for detecting CpG methylation in G4-forming oligonucleotides based on the structural differences between methylated and unmethylated G4 DNAs. The differences in G4 topologies due to CpG methylation can be discriminated by G4 ligands. We performed a binding assay between methylated or unmethylated G4 DNAs and G4 ligands. The binding abilities of fluorescent G4 ligands to BCL-2, HRAS1, HRAS2, VEGF G4-forming sequences were examined by fluorescence-based microtiter plate assay. The differences in fluorescence intensities between methylated and unmethylated G4 DNAs were statistically significant. In addition to fluorescence detection, the binding of G4 ligand to DNA was detected by chemiluminescence. A significant difference was also detected in chemiluminescence intensity between methylated and unmethylated DNA. This is the first study on the detection of CpG methylation in G4 structures, focusing on structural changes using G4 ligands.

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Głuszyńska, Agata, Bernard Juskowiak, and Błażej Rubiś. "Binding Study of the Fluorescent Carbazole Derivative with Human Telomeric G-Quadruplexes." Molecules 23, no. 12 (November 30, 2018): 3154. http://dx.doi.org/10.3390/molecules23123154.

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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.

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Tsukakoshi, Kaori, Yuri Ikuta, Koichi Abe, Wataru Yoshida, Keisuke Iida, Yue Ma, Kazuo Nagasawa, Koji Sode, and Kazunori Ikebukuro. "Structural regulation by a G-quadruplex ligand increases binding abilities of G-quadruplex-forming aptamers." Chemical Communications 52, no. 85 (2016): 12646–49. http://dx.doi.org/10.1039/c6cc07552e.

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Bhadane, Rajendra, Rupali Bhadane, and Dhananjay Meshram. "Insights of potential G-quadruplex sequences in telomeres and proto-oncogenes." Archive of Oncology 21, no. 3-4 (2013): 118–24. http://dx.doi.org/10.2298/aoo1304118b.

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Guanine rich sequences have the ability to fold into stable 4 stranded structures called G-quadruplex under physiological concentrations of Na+ or K+. G-quadruplexes are found in telomeres, being stable structures under the control of telomerase binding proteins. They are also identified throughout the genome and are enriched in promoter regions of protein coding genes, upstream and downstream of the transcription initiation sites. A number of these promoter quadruplexes have been investigated for several proto-oncogenes. The formation of these quadruplexes can lead to chemical intervention of gene expression using a G-quadruplex binding ligand. We review location, configuration, and stabilization of these quadruplexes in some of the important promoters with regards to their potential as anticancer target.

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Moreira, David, Daniela Leitão, Jéssica Lopes-Nunes, Tiago Santos, Joana Figueiredo, André Miranda, Daniela Alexandre, Cândida Tomaz, Jean-Louis Mergny, and Carla Cruz. "G-Quadruplex Aptamer-Ligand Characterization." Molecules 27, no. 20 (October 11, 2022): 6781. http://dx.doi.org/10.3390/molecules27206781.

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In this work we explore the structure of a G-rich DNA aptamer termed AT11-L2 (TGGTGGTGGTTGTTGTTGGTGGTGGTGGT; derivative of AT11) by evaluating the formation and stability of G-quadruplex (G4) conformation under different experimental conditions such as KCl concentration, temperature, and upon binding with a variety of G4 ligands (360A, BRACO-19, PDS, PhenDC3, TMPyP4). We also determined whether nucleolin (NCL) can be a target of AT11-L2 G4. Firstly, we assessed by circular dichroism, UV and NMR spectroscopies the formation of G4 by AT11-L2. We observed that, for KCl concentrations of 65 mM or less, AT11-L2 adopts hybrid or multiple topologies. In contrast, a parallel topology predominates for buffer containing 100 mM of KCl. The Tm of AT11-L2 in 100 mM of KCl is 38.9 °C, proving the weak stability of this sequence. We also found that upon titration with two molar equivalents of 360A, BRACO-19 and PhenDC3, the G4 is strongly stabilized and its topology is maintained, while the addition of 3.5 molar equivalents of TMPyP4 promotes the disruption of G4. The KD values between AT11-L2 G4, ligands and NCL were obtained by fluorescence titrations and are in the range of µM for ligand complexes and nM when adding NCL. In silico studies suggest that four ligands bind to the AT11-L2 G4 structure by stacking interactions, while the RBD1,2 domains of NCL interact preferentially with the thymines of AT11-L2 G4. Finally, AT11-L2 G4 co-localized with NCL in NCL-positive tongue squamous cell carcinoma cell line.

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Desai, Nakshi, Viraj Shah, and Bhaskar Datta. "Assessing G4-Binding Ligands In Vitro and in Cellulo Using Dimeric Carbocyanine Dye Displacement Assay." Molecules 26, no. 5 (March 5, 2021): 1400. http://dx.doi.org/10.3390/molecules26051400.

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G-quadruplexes (G4) are the most actively studied non-canonical secondary structures formed by contiguous repeats of guanines in DNA or RNA strands. Small molecule mediated targeting of G-quadruplexes has emerged as an attractive tool for visualization and stabilization of these structures inside the cell. Limited number of DNA and RNA G4-selective assays have been reported for primary ligand screening. A combination of fluorescence spectroscopy, AFM, CD, PAGE, and confocal microscopy have been used to assess a dimeric carbocyanine dye B6,5 for screening G4-binding ligands in vitro and in cellulo. The dye B6,5 interacts with physiologically relevant DNA and RNA G4 structures, resulting in fluorescence enhancement of the molecule as an in vitro readout for G4 selectivity. Interaction of the dye with G4 is accompanied by quadruplex stabilization that extends its use in primary screening of G4 specific ligands. The molecule is cell permeable and enables visualization of quadruplex dominated cellular regions of nucleoli using confocal microscopy. The dye is displaced by quarfloxin in live cells. The dye B6,5 shows remarkable duplex to quadruplex selectivity in vitro along with ligand-like stabilization of DNA G4 structures. Cell permeability and response to RNA G4 structures project the dye with interesting theranostic potential. Our results validate that B6,5 can serve the dual purpose of visualization of DNA and RNA G4 structures and screening of G4 specific ligands, and adds to the limited number of probes with such potential.

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11

Harikrishna, S., Saikiran Kotaru, and P. I. Pradeepkumar. "Ligand-induced conformational preorganization of loops of c-MYC G-quadruplex DNA and its implications in structure-specific drug design." Molecular BioSystems 13, no. 8 (2017): 1458–68. http://dx.doi.org/10.1039/c7mb00175d.

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12

Heddi, Brahim, Vee Vee Cheong, Herry Martadinata, and Anh Tuân Phan. "Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex." Proceedings of the National Academy of Sciences 112, no. 31 (July 20, 2015): 9608–13. http://dx.doi.org/10.1073/pnas.1422605112.

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Four-stranded nucleic acid structures called G-quadruplexes have been associated with important cellular processes, which should require G-quadruplex–protein interaction. However, the structural basis for specific G-quadruplex recognition by proteins has not been understood. The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also named DHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identified an 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptide bound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallel G-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps the G-quadruplex using three-anchor-point electrostatic interactions between three positively charged amino acids and negatively charged phosphate groups. This binding mode is strikingly similar to that of most ligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simple and efficient way to specifically target G-quadruplex structures.

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13

Haider, Shozeb M., and Stephen Neidle. "A molecular model for drug binding to tandem repeats of telomeric G-quadruplexes." Biochemical Society Transactions 37, no. 3 (May 20, 2009): 583–88. http://dx.doi.org/10.1042/bst0370583.

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The extreme 3′-ends of human telomeres consist of 150–250 nucleotides of single-stranded DNA sequence together with associated proteins. Small-molecule ligands can compete with these proteins and induce a conformational change in the DNA to a four-stranded quadruplex arrangement, which is also no longer a substrate for the telomerase enzyme. The modified telomere ends provide signals to the DNA-damage-response system and trigger senescence and apoptosis. Experimental structural data are available on such quadruplex complexes comprising up to four telomeric DNA repeats, but not on longer systems that are more directly relevant to the single-stranded overhang in human cells. The present paper reports on a molecular modelling study that uses Molecular Dynamics simulation methods to build dimer and tetramer quadruplex repeats. These incorporate ligand-binding sites and are models for overhang–ligand complexes.

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Pirota, Valentina, Matteo Nadai, Filippo Doria, and Sara Richter. "Naphthalene Diimides as Multimodal G-Quadruplex-Selective Ligands." Molecules 24, no. 3 (January 24, 2019): 426. http://dx.doi.org/10.3390/molecules24030426.

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G-quadruplexes are four-stranded nucleic acids structures that can form in guanine-rich sequences. Following the observation that G-quadruplexes are particularly abundant in genomic regions related to cancer, such as telomeres and oncogenes promoters, several G-quadruplex-binding molecules have been developed for therapeutic purposes. Among them, naphthalene diimide derivatives have reported versatility, consistent selectivity and high affinity toward the G-quadruplex structures. In this review, we present the chemical features, synthesis and peculiar optoelectronic properties (absorption, emission, redox) that make naphtalene diimides so versatile for biomedical applications. We present the latest developments on naphthalene diimides as G-quadruplex ligands, focusing on their ability to bind G-quadruplexes at telomeres and oncogene promoters with consequent anticancer activity. Their different binding modes (reversible versus irreversible/covalent) towards G-quadruplexes and their additional use as antimicrobial agents are also presented and discussed.

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Oliva, Rosario, Sanjib Mukherjee, Magiliny Manisegaran, Marco Campanile, Pompea Del Vecchio, Luigi Petraccone, and Roland Winter. "Binding Properties of RNA Quadruplex of SARS-CoV-2 to Berberine Compared to Telomeric DNA Quadruplex." International Journal of Molecular Sciences 23, no. 10 (May 19, 2022): 5690. http://dx.doi.org/10.3390/ijms23105690.

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Previous studies suggest that berberine, an isoquinoline alkaloid, has antiviral potential and is a possible therapeutic candidate against SARS-CoV-2. The molecular underpinnings of its action are still unknown. Potential targets include quadruplexes (G4Q) in the viral genome as they play a key role in modulating the biological activity of viruses. While several DNA-G4Q structures and their binding properties have been elucidated, RNA-G4Qs such as RG-1 of the N-gene of SARS-CoV-2 are less explored. Using biophysical techniques, the berberine binding thermodynamics and the associated conformational and hydration changes of RG-1 could be characterized and compared with human telomeric DNA-G4Q 22AG. Berberine can interact with both quadruplexes. Substantial changes were observed in the interaction of berberine with 22AG and RG-1, which adopt different topologies that can also change upon ligand binding. The strength of interaction and the thermodynamic signatures were found to dependent not only on the initial conformation of the quadruplex, but also on the type of salt present in solution. Since berberine has shown promise as a G-quadruplex stabilizer that can modulate viral gene expression, this study may also contribute to the development of optimized ligands that can discriminate between binding to DNA and RNA G-quadruplexes.

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Sun, Zhi-Yin, Xiao-Na Wang, Sui-Qi Cheng, Xiao-Xuan Su, and Tian-Miao Ou. "Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction." Molecules 24, no. 3 (January 22, 2019): 396. http://dx.doi.org/10.3390/molecules24030396.

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G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.

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Moraca, Federica, Jussara Amato, Francesco Ortuso, Anna Artese, Bruno Pagano, Ettore Novellino, Stefano Alcaro, Michele Parrinello, and Vittorio Limongelli. "Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations." Proceedings of the National Academy of Sciences 114, no. 11 (February 23, 2017): E2136—E2145. http://dx.doi.org/10.1073/pnas.1612627114.

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G-quadruplexes (G4s) are higher-order DNA structures typically present at promoter regions of genes and telomeres. Here, the G4 formation decreases the replicative DNA at each cell cycle, finally leading to apoptosis. The ability to control this mitotic clock, particularly in cancer cells, is fascinating and passes through a rational understanding of the ligand/G4 interaction. We demonstrate that an accurate description of the ligand/G4 binding mechanism is possible using an innovative free-energy method called funnel-metadynamics (FM), which we have recently developed to investigate ligand/protein interaction. Using FM simulations, we have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 (d[AG3(T2AG3)3]), computing also the binding free-energy landscape. Two ligand binding modes have been identified as the lowest energy states. Furthermore, we have found prebinding sites, which are preparatory to reach the final binding mode. In our simulations, the ions and the water molecules have been explicitly represented and the energetic contribution of the solvent during ligand binding evaluated. Our theoretical results provide an accurate estimate of the absolute ligand/DNA binding free energy (ΔGb0 = −10.3 ± 0.5 kcal/mol) that we validated through steady-state fluorescence binding assays. The good agreement between the theoretical and experimental value demonstrates that FM is a most powerful method to investigate ligand/DNA interaction and can be a useful tool for the rational design also of G4 ligands.

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Platella, Chiara, Rosa Gaglione, Ettore Napolitano, Angela Arciello, Valentina Pirota, Filippo Doria, Domenica Musumeci, and Daniela Montesarchio. "DNA Binding Mode Analysis of a Core-Extended Naphthalene Diimide as a Conformation-Sensitive Fluorescent Probe of G-Quadruplex Structures." International Journal of Molecular Sciences 22, no. 19 (September 30, 2021): 10624. http://dx.doi.org/10.3390/ijms221910624.

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G-quadruplex existence was proved in cells by using both antibodies and small molecule fluorescent probes. However, the G-quadruplex probes designed thus far are structure- but not conformation-specific. Recently, a core-extended naphthalene diimide (cex-NDI) was designed and found to provide fluorescent signals of markedly different intensities when bound to G-quadruplexes of different conformations or duplexes. Aiming at evaluating how the fluorescence behaviour of this compound is associated with specific binding modes to the different DNA targets, cex-NDI was here studied in its interaction with hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex models by biophysical techniques, molecular docking, and biological assays. cex-NDI showed different binding modes associated with different amounts of stacking interactions with the three DNA targets. The preferential binding sites were the groove, outer quartet, or intercalative site of the hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex, respectively. Interestingly, our data show that the fluorescence intensity of DNA-bound cex-NDI correlates with the amount of stacking interactions formed by the ligand with each DNA target, thus providing the rationale behind the conformation-sensitive properties of cex-NDI and supporting its use as a fluorescent probe of G-quadruplex structures. Notably, biological assays proved that cex-NDI mainly localizes in the G-quadruplex-rich nuclei of cancer cells.

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Aznauryan, Mikayel, Sofie Louise Noer, Camilla W. Pedersen, Jean‐Louis Mergny, Marie‐Paule Teulade‐Fichou, and Victoria Birkedal. "Ligand Binding to Dynamically Populated G‐Quadruplex DNA." ChemBioChem 22, no. 10 (March 4, 2021): 1811–17. http://dx.doi.org/10.1002/cbic.202000792.

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Nagesh, Narayana, and Arumugam Ganesh Kumar. "Interaction of TMPyP4, TMPyP3, and TMPyP2 with Intramolecular G-Quadruplex Formed by Promoter Region of Bcl2 and KRAS NHPPE." ISRN Biophysics 2012 (February 7, 2012): 1–12. http://dx.doi.org/10.5402/2012/786596.

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Oncogenes are rich in guanine and capable of forming quadruplex structure. Promoter regions oncogenes such as Bcl2 and KRAS NHPPE are rich in guanine content and they can form quadruplex structures. Alterations in the mode and nature of molecular binding to DNA, certainly has effect on the posttranscriptional activities. Recent experiments indicate that structure of quadruplex complex and ligand has predominant role on ligand-quadruplex DNA interaction. In order to understand the nature of each ligand interaction with quadruplex DNA, Bcl2, KRAS NHPPE quadruplex DNA interaction with three porphyrin was studied using spectroscopy, microcalorimetry and mass spectrometry. Our studies, indicate that mode of ligand interaction varies with structure, environment and concentration of ligand. Fluorescence quenching experiments show that TMPyP4 interaction is ligand concentration dependent. Job plots and ITC experiments demonstrate that four molecules of TMPyP4 and two molecules of TMPyP3, TMPyP2 interact with each quadruplex complex. Through ITC titrations, ligand binding constant are higher for TMPyP4 (≈107 M−1) compared to TMPyP3, TMPyP2 (≈105 M−1). ESI-MS experiments confirm the stoichiometry of TMPyP4 : 39Bcl2 is 4 : 1 at saturation and it is 2 : 1 in case of KRAS NHPPE quadruplex.

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Masson, Thibaut, Corinne Landras Guetta, Eugénie Laigre, Anne Cucchiarini, Patricia Duchambon, Marie-Paule Teulade-Fichou, and Daniela Verga. "BrdU immuno-tagged G-quadruplex ligands: a new ligand-guided immunofluorescence approach for tracking G-quadruplexes in cells." Nucleic Acids Research 49, no. 22 (December 7, 2021): 12644–60. http://dx.doi.org/10.1093/nar/gkab1166.

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Abstract G-quadruplexes (G4s) are secondary structures forming in G-rich nucleic acids. G4s are assumed to play critical roles in biology, nonetheless their detection in cells is still challenging. For tracking G4s, synthetic molecules (G4 ligands) can be used as reporters and have found wide application for this purpose through chemical functionalization with a fluorescent tag. However, this approach is limited by a low-labeling degree impeding precise visualization in specific subcellular regions. Herein, we present a new visualization strategy based on the immuno-recognition of 5-bromo-2′-deoxyuridine (5-BrdU) modified G4 ligands, functionalized prior- or post-G4-target binding by CuAAC. Remarkably, recognition of the tag by antibodies leads to the detection of the modified ligands exclusively when bound to a G4 target both in vitro, as shown by ELISA, and in cells, thereby providing a highly efficient G4-ligand Guided Immunofluorescence Staining (G4-GIS) approach. The obtained signal amplification revealed well-defined fluorescent foci located in the perinuclear space and RNase treatment revealed the preferential binding to G4-RNA. Furthermore, ligand treatment affected significantly BG4 foci formation in cells. Our work headed to the development of a new imaging approach combining the advantages of immunostaining and G4-recognition by G4 ligands leading to visualization of G4/ligands species in cells with unrivaled precision and sensitivity.

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Machireddy, Babitha, Holli-Joi Sullivan, and Chun Wu. "Binding of BRACO19 to a Telomeric G-Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent." Molecules 24, no. 6 (March 13, 2019): 1010. http://dx.doi.org/10.3390/molecules24061010.

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Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 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, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19′s binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19′s groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism.

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Han, Ji Ho, and Moon Jung Song. "인간 허피스바이러스에 대한 G-quadruplex 결합 리간드의 항바이러스 효과." Institute of Life Science and Natural Resources 30 (December 31, 2022): 23–31. http://dx.doi.org/10.33147/lsnrr.2022.30.1.23.

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G-quadruplexes (G4s) are noncanonical secondary nucleic acid structures constituted by stacking of guanine rich planar shaped tetrad formations that form a complex. G4s are implicated for various important roles in key cellular processes transcription, translation, telomere maintenance, epigenetic regulation, replication, and recombination. G-quadruplexes were first discovered as important structures in oncology, but for the past decade its relevance in viruses is becoming more evident. Human herpesviruses are DNA viruses of the Herpesviridae family and are unique in characteristic with two types of infection which can be distinguished by lytic and latency establishment in the host. During latency the virus maintains lifelong dormancy and intermittently undergoes reactivation, causing the host medical problems. Recently there are increasing number of reports regarding role of G4s in viral genomes and the potential antiviral efficacy of G4 ligands, including G4s in latency. Many results suggest viral G4s play significant roles in the virus life cycle and treatment of G4 ligands exhibit antiviral activities in both lytic and latent infections. In this review, the importance of G4s in herpesvirus genomes will be introduced with the potent G4 ligands used to study these mechanisms and finally explain the distinct functional properties of each G4 ligands.

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Pagano, Bruno, Iolanda Fotticchia, Stefano De Tito, Carlo A. Mattia, Luciano Mayol, Ettore Novellino, Antonio Randazzo, and Concetta Giancola. "Selective Binding of Distamycin A Derivative to G-Quadruplex Structure [d(TGGGGT)]4." Journal of Nucleic Acids 2010 (2010): 1–7. http://dx.doi.org/10.4061/2010/247137.

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Guanine-rich nucleic acid sequences can adopt G-quadruplex structures stabilized by layers of four Hoogsteen-paired guanine residues. Quadruplex-prone sequences are found in many regions of human genome and in the telomeres of all eukaryotic organisms. Since small molecules that target G-quadruplexes have been found to be effective telomerase inhibitors, the identification of new specific ligands for G-quadruplexes is emerging as a promising approach to develop new anticancer drugs. Distamycin A is known to bind to AT-rich sequences of duplex DNA, but it has recently been shown to interact also with G-quadruplexes. Here, isothermal titration calorimetry (ITC) and NMR techniques have been employed to characterize the interaction between a dicationic derivative of distamycin A (compound1) and the [d(TGGGGT)]4quadruplex. Additionally, to compare the binding behaviour of netropsin and compound1to the same target, a calometric study of the interaction between netropsin and [d(TGGGGT)]4has been performed. Experiments show that netropsin and compound1are able to bind to [d(TGGGGT)]4with good affinity and comparable thermodynamic profiles. In both cases the interactions are entropically driven processes with a small favourable enthalpic contribution. Interestingly, the structural modifications of compound1decrease the affinity of the ligand toward the duplex, enhancing the selectivity.

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Dallavalle, Sabrina, Roberto Artali, Salvatore Princiotto, Loana Musso, Gigliola Borgonovo, and Stefania Mazzini. "Investigation of the Interaction between Aloe vera Anthraquinone Metabolites and c-Myc and C-Kit G-Quadruplex DNA Structures." International Journal of Molecular Sciences 23, no. 24 (December 16, 2022): 16018. http://dx.doi.org/10.3390/ijms232416018.

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G-quadruplexes are nucleotide sequences present in the promoter region of numerous oncogenes, having a key role in the suppression of gene transcription. Recently, the binding of anthraquinones from Aloe vera to G-quadruplex structures has been studied through various physico-chemical techniques. Intrigued by the reported results, we investigated the affinity of aloe emodin, aloe emodin-8-glucoside, and aloin to selected G-quadruplex nucleotide sequences by NMR spectroscopy. The structural determinants for the formation of the ligand/nucleotide complexes were elucidated and a model of the interactions between the tested compounds and C-Kit and c-Myc G-quadruplex DNA structures was built by integrated NMR and molecular modeling studies. Overall, the obtained results confirmed and implemented the previously reported findings, pointing out the complementarity of the different approaches and their contribution to a more detailed overview of the ligand/nucleotide complex formation. Furthermore, the proposed models of interaction could pave the way to the design of new nature-derived compounds endowed with increased G-quadruplex stabilizing activity.

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Doria, Filippo, Valentina Pirota, Michele Petenzi, Marie-Paule Teulade-Fichou, Daniela Verga, and Mauro Freccero. "Oxadiazole/Pyridine-Based Ligands: A Structural Tuning for Enhancing G-Quadruplex Binding." Molecules 23, no. 9 (August 28, 2018): 2162. http://dx.doi.org/10.3390/molecules23092162.

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Non-macrocyclic heteroaryls represent a valuable class of ligands for nucleic acid recognition. In this regard, non-macrocyclic pyridyl polyoxazoles and polyoxadiazoles were recently identified as selective G-quadruplex stabilizing compounds with high cytotoxicity and promising anticancer activity. Herein, we describe the synthesis of a new family of heteroaryls containing oxadiazole and pyridine moieties targeting DNA G-quadruplexes. To perform a structure–activity analysis identifying determinants of activity and selectivity, we followed a convergent synthetic pathway to modulate the nature and number of the heterocycles (1,3-oxazole vs. 1,2,4-oxadiazole and pyridine vs. benzene). Each ligand was evaluated towards secondary nucleic acid structures, which have been chosen as a prototype to mimic cancer-associated G-quadruplex structures (e.g., the human telomeric sequence, c-myc and c-kit promoters). Interestingly, heptapyridyl-oxadiazole compounds showed preferential binding towards the telomeric sequence (22AG) in competitive conditions vs. duplex DNA. In addition, G4-FID assays suggest a different binding mode from the classical stacking on the external G-quartet. Additionally, CD titrations in the presence of the two most promising compounds for affinity, TOxAzaPy and TOxAzaPhen, display a structural transition of 22AG in K-rich buffer. This investigation suggests that the pyridyl-oxadiazole motif is a promising recognition element for G-quadruplexes, combining seven heteroaryls in a single binding unit.

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Di Leva, Francesco Saverio, Ettore Novellino, Andrea Cavalli, Michele Parrinello, and Vittorio Limongelli. "Mechanistic insight into ligand binding to G-quadruplex DNA." Nucleic Acids Research 42, no. 9 (April 21, 2014): 5447–55. http://dx.doi.org/10.1093/nar/gku247.

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Bouzada, David, Iria Salvadó, Ghofrane Barka, Gustavo Rama, José Martínez-Costas, Romina Lorca, Álvaro Somoza, Manuel Melle-Franco, M. Eugenio Vázquez, and Miguel Vázquez López. "Selective G-quadruplex binding by oligoarginine-Ru(dppz) metallopeptides." Chemical Communications 54, no. 6 (2018): 658–61. http://dx.doi.org/10.1039/c7cc08286j.

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We demonstrate that both the R₈ functionalization and its interplay with the ancillary ligand have and an important role in the G-quadruplex recognition process by Ru(dppz) metallopeptides.

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Salgado, Gilmar F., Christian Cazenave, Abdelaziz Kerkour, and Jean-Louis Mergny. "G-quadruplex DNA and ligand interaction in living cells using NMR spectroscopy." Chemical Science 6, no. 6 (2015): 3314–20. http://dx.doi.org/10.1039/c4sc03853c.

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Scott, Lily, and Tigran V. Chalikian. "Stabilization of G-Quadruplex-Duplex Hybrid Structures Induced by Minor Groove-Binding Drugs." Life 12, no. 4 (April 18, 2022): 597. http://dx.doi.org/10.3390/life12040597.

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Once it had been realized that G-quadruplexes exist in the cell and are involved in regulation of genomic processes, the quest for ligands recognizing these noncanonical structures was underway. Many organic compounds that tightly associate with G-quadruplexes have been identified. However, the specificity of G-quadruplex-binding ligands towards individual structures remains problematic, as the common recognition element of these ligands is the G-tetrad. In this paper, we focus on G-quadruplex-duplex hybrids (QDH) containing a hairpin duplex incorporated as a stem-loop into the G-quadruplex core. The presence of a stem-loop renders QDH amenable to sequence-specific recognition by duplex-binding drugs. Should the thermodynamic crosstalk between the stem-loop and the tetraplex core be sufficiently strong, the drug binding to the loop would lead to the stabilization of the entire structure. We studied the stabilizing influence of the minor groove-binders netropsin and Hoechst 33258 on a family of QDH structures, as well as a G-quadruplex and a hairpin modeling the G-quadruplex core and the stem-loop of the QDH’s. We found that the binding of either drug results in an enhancement of the thermal stability of all DNA structures, as expressed by increases in the melting temperature, TM. Analysis of the hierarchical order of increases in TM revealed that the drug-induced stabilization arises from drug binding to the G-quadruplex domain of a QDH and the stem-loop, if the latter contains an all-AT binding site. This result attests to the thermodynamic crosstalk between the stem-loop and the tetraplex core of a QDH. Given the existing library of minor groove-binding drugs recognizing mixed A·T and G·C DNA sequences, our results point to an untapped avenue for sequence-specific recognition of QDH structures in vitro and, possibly, in vivo; thereby, opening the way for selective stabilization of four-stranded DNA structures at predetermined genomic loci, with implications for the control of genomic events.

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Gu, Hui-Ping, Sen Lin, Ming Xu, Hai-Yi Yu, Xiao-Jun Du, You-Yi Zhang, Gu Yuan, and Wei Gao. "Up-Regulating Relaxin Expression by G-Quadruplex Interactive Ligand to Achieve Antifibrotic Action." Endocrinology 153, no. 8 (June 6, 2012): 3692–700. http://dx.doi.org/10.1210/en.2012-1114.

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Myocardial fibrosis is a key pathological change in a variety of heart diseases contributing to the development of heart failure, arrhythmias, and sudden death. Recent studies have shown that relaxin prevents and reverses cardiac fibrosis. Endogenous expression of relaxin was elevated in the setting of heart disease; the extent of such up-regulation, however, is insufficient to exert compensatory actions, and the mechanism regulating relaxin expression is poorly defined. In the rat relaxin-1 (RLN1, Chr1) gene promoter region we found presence of repeated guanine (G)-rich sequences, which allowed formation and stabilization of G-quadruplexes with the addition of a G-quadruplex interactive ligand berberine. The G-rich sequences and the G-quadruplexes were localized adjacent to the binding motif of signal transducer and activator of transcription (STAT)3, which negatively regulates relaxin expression. Thus, we hypothesized that the formation and stabilization of G-quadruplexes by berberine could influence relaxin expression. We found that berberine-induced formation of G-quadruplexes did increase relaxin gene expression measured at mRNA and protein levels. Formation of G-quadruplexes significantly reduced STAT3 binding to the promoter of relaxin gene. This was associated with consequent increase in the binding of RNA polymerase II and STAT5a to relaxin gene promoter. In cardiac fibroblasts and rats treated with angiotensin II, berberine was found to suppress fibroblast activation, collagen synthesis, and extent of cardiac fibrosis through up-regulating relaxin. The antifibrotic action of berberine in vitro and in vivo was similar to that by exogenous relaxin. Our findings document a novel therapeutic strategy for fibrosis through up-regulating expression of endogenous relaxin.

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Chilka, Pallavi, Nakshi Desai, and Bhaskar Datta. "Small Molecule Fluorescent Probes for G- Quadruplex Visualization as Potential Cancer Theranostic Agents." Molecules 24, no. 4 (February 19, 2019): 752. http://dx.doi.org/10.3390/molecules24040752.

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G-quadruplexes have gained prominence over the past two decades for their role in gene regulation, control of anti-tumour activity and ageing. The physiological relevance and significance of these non-canonical structures in the context of cancer has been reviewed several times. Putative roles of G-quadruplexes in cancer prognosis and pathogenesis have spurred the search for small molecule ligands that are capable of binding and modulating the effect of such structures. On a related theme, small molecule fluorescent probes have emerged that are capable of selective recognition of G-quadruplex structures. These have opened up the possibility of direct visualization and tracking of such structures. In this review we outline recent developments on G-quadruplex specific small molecule fluorescent probes for visualizing G-quadruplexes. The molecules represent a variety of structural scaffolds, mechanism of quadruplex-recognition and fluorescence signal transduction. Quadruplex selectivity and in vivo imaging potential of these molecules places them uniquely as quadruplex-theranostic agents in the predominantly cancer therapeutic context of quadruplex-selective ligands.

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Zhong, Yi-ning, Yan Zhang, Yun-qiong Gu, Shi-yun Wu, Wen-ying Shen, and Ming-xiong Tan. "NovelFeIIandCoIIComplexes of Natural Product Tryptanthrin: Synthesis and Binding with G-Quadruplex DNA." Bioinorganic Chemistry and Applications 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/5075847.

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Tryptanthrin is one of the most important members of indoloquinoline alkaloids. We obtained this alkaloid fromIsatis. Two novelFeIIandCoIIcomplexes of tryptanthrin were first synthesized. Single-crystal X-ray diffraction analyses show that these complexes display distorted four-coordinated tetrahedron geometry via two heterocyclic nitrogen and oxygen atoms from tryptanthrin ligand. Binding with G-quadruplex DNA properties revealed that both complexes were found to exhibit significant interaction with G-quadruplex DNA. This study may potentially serve as the basis of future rational design of metal-based drugs from natural products that target the G-quadruplex DNA.

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Ishikawa, Ryo, Mizuho Yasuda, Shogo Sasaki, Yue Ma, Kazuo Nagasawa, and Masayuki Tera. "Stabilization of telomeric G-quadruplex by ligand binding increases susceptibility to S1 nuclease." Chemical Communications 57, no. 59 (2021): 7236–39. http://dx.doi.org/10.1039/d1cc03294a.

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Maheswari, Palanisamy Uma, Renuga Duraisamy, Murugesan Kanagavel, Kalimuthusamy Natarajaseenivasan, Kadhar Mohamed Meera Sheriffa Begum, and Ruckmani Kandasamy. "Telomere DNA Binding, Cleavage and Anticancer Activity of [Cu(phendione)(Hpyramol)Cl]." Current Chemical Biology 13, no. 2 (July 12, 2019): 171–82. http://dx.doi.org/10.2174/2212796813666190214112129.

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Background:The ligand Hpyramol is a redox active, which on coordination with Cu(II) cleaves DNA without any added reductant. Another ligand phendione is known for its wide application towards anticancer activities. We combined the ligands with CuCl2 to have an intercalation moiety and a redox active ligand in participation towards telomere DNA cleavage and anticancer activity.Objective:In this study, our aim is to interact it with Human telomere DNA and to see their effects on cancer cells.Methods:The complex [Cu(L)(L’)Cl] has interacted with the human telomere DNA sequence (TTAGGG), HTelo20. The HTelo20 was stabilized under both parallel and antiparallel G-quadruplex conformations and the complex [Cu(L)(L’)Cl] has interacted followed by circular dichroism spectroscopy and gel electrophoresis.Results:The parallel G-quadruplex and randomly coiled conformations of HTelo20 were easily cleaved than the anti-parallel G-quadruplex conformation. The nature of DNA cleavage was found to be oxidative rather hydrolytic. The formation of phenoxyl radical species under electrochemical and controlled potential electrolysis conditions by the complex [Cu(L)(L’)Cl] proves the possibility of oxidative nature of DNA cleavage. The comet assay also proves the DNA cleavage induced by the complex [Cu(L)(L’)Cl] inside the nucleus of HeLa cancer cells.Conclusion:The complex [Cu(L)(L’)Cl] was tested for anticancer activity, induced by ROS and DNA cleavage. The IC50 values resulted in nanomolar concentrations with selected cancer cell lines. Relatively the Cu complex shows less toxicity with the normal cell line L132.

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Chiorcea-Paquim, Ana-Maria, Ramon Eritja, and Ana Maria Oliveira-Brett. "Electrochemical and AFM Characterization of G-Quadruplex Electrochemical Biosensors and Applications." Journal of Nucleic Acids 2018 (2018): 1–20. http://dx.doi.org/10.1155/2018/5307106.

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Guanine-rich DNA sequences are able to form G-quadruplexes, being involved in important biological processes and representing smart self-assembling nanomaterials that are increasingly used in DNA nanotechnology and biosensor technology. G-quadruplex electrochemical biosensors have received particular attention, since the electrochemical response is particularly sensitive to the DNA structural changes from single-stranded, double-stranded, or hairpin into a G-quadruplex configuration. Furthermore, the development of an increased number of G-quadruplex aptamers that combine the G-quadruplex stiffness and self-assembling versatility with the aptamer high specificity of binding to a variety of molecular targets allowed the construction of biosensors with increased selectivity and sensitivity. This review discusses the recent advances on the electrochemical characterization, design, and applications of G-quadruplex electrochemical biosensors in the evaluation of metal ions, G-quadruplex ligands, and other small organic molecules, proteins, and cells. The electrochemical and atomic force microscopy characterization of G-quadruplexes is presented. The incubation time and cations concentration dependence in controlling the G-quadruplex folding, stability, and nanostructures formation at carbon electrodes are discussed. Different G-quadruplex electrochemical biosensors design strategies, based on the DNA folding into a G-quadruplex, the use of G-quadruplex aptamers, or the use of hemin/G-quadruplex DNAzymes, are revisited.

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Comez, L., F. Bianchi, V. Libera, M. Longo, C. Petrillo, F. Sacchetti, F. Sebastiani, et al. "Polymorphism of human telomeric quadruplexes with drugs: a multi-technique biophysical study." Physical Chemistry Chemical Physics 22, no. 20 (2020): 11583–92. http://dx.doi.org/10.1039/d0cp01483d.

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Ribaudo, Giovanni, Alberto Ongaro, Erika Oselladore, Giuseppe Zagotto, Maurizio Memo, and Alessandra Gianoncelli. "9,10-Bis[(4-(2-hydroxyethyl)piperazine-1-yl)prop-2-yne-1-yl]anthracene: Synthesis and G-quadruplex Selectivity." Molbank 2020, no. 2 (May 22, 2020): M1138. http://dx.doi.org/10.3390/m1138.

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G-quadruplex DNA is the target of several natural and synthetic small molecules with antiproliferative and antiviral activity. We here report the synthesis through Sonogashira reaction and A3 coupling of a disubstituted anthracene derivative, 9,10-bis[(4-(2-hydroxyethyl)piperazine-1-yl)prop-2-yne-1-yl]anthracene. The binding of this compound to G-quadruplex and double stranded DNA sequences was evaluated using electrospray ionization mass spectrometry (ESI-MS), demonstrating selectivity for the first structure. The interaction pattern of the ligand with G-quadruplex was investigated by molecular docking and stacking was found to be the preferred binding mode.

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Smith, N. M., B. Corry, K. Swaminathan Iyer, M. Norret, and C. L. Raston. "A microfluidic platform to synthesise a G-quadruplex binding ligand." Lab on a Chip 9, no. 14 (2009): 2021. http://dx.doi.org/10.1039/b902986a.

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Ong, Chi Wi, Meng-Chi Liu, Kun-Da Lee, Keng Wei Chang, Ya-Ting Yang, Hung-Wei Tung, and Keith R. Fox. "Synthesis of bisquinoline–pyrrole oligoamide as G-quadruplex binding ligand." Tetrahedron 68, no. 27-28 (July 2012): 5453–57. http://dx.doi.org/10.1016/j.tet.2012.05.001.

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Yu, Hui, Yan Li Wang, Xiao Yin Zhao, and Wen Zhang. "Synthetic Small Molecules Targeting G-Quadruplexes and their Application." Advanced Materials Research 1088 (February 2015): 507–13. http://dx.doi.org/10.4028/www.scientific.net/amr.1088.507.

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G-quadruplex is expected to be a promising target for drug design. The manually synthesized small-molecule compounds are able to induce the formation of and stabilize G-quadruplexes. In this paper, we summarize the current understanding of the structure of G-quadruplexes, the binding mode of G-quadruplexes and small-molecule ligands, and important synthesized small molecules targeting G-quadruplexes as potential drugs.

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Le, D. D., M. Di Antonio, L. K. M. Chan, and S. Balasubramanian. "G-quadruplex ligands exhibit differential G-tetrad selectivity." Chemical Communications 51, no. 38 (2015): 8048–50. http://dx.doi.org/10.1039/c5cc02252e.

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Wang, Yu-Huan, Qian-Fan Yang, Xiao Lin, Die Chen, Zhi-Yin Wang, Bin Chen, Hua-Yi Han, et al. "G4LDB 2.2: a database for discovering and studying G-quadruplex and i-Motif ligands." Nucleic Acids Research 50, no. D1 (October 29, 2021): D150—D160. http://dx.doi.org/10.1093/nar/gkab952.

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Abstract Noncanonical nucleic acid structures, such as G-quadruplex (G4) and i-Motif (iM), have attracted increasing research interests because of their unique structural and binding properties, as well as their important biological activities. To date, thousands of small molecules that bind to varying G4/iM structures have been designed, synthesized and tested for diverse chemical and biological uses. Because of the huge potential and increasing research interests on G4-targeting ligands, we launched the first G4 ligand database G4LDB in 2013. Here, we report a new version, termed G4LDB 2.2 (http://www.g4ldb.com), with upgrades in both content and function. Currently, G4LDB2.2 contains >3200 G4/iM ligands, ∼28 500 activity entries and 79 G4–ligand docking models. In addition to G4 ligand library, we have also added a brand new iM ligand library to G4LDB 2.2, providing a comprehensive view of quadruplex nucleic acids. To further enhance user experience, we have also redesigned the user interface and optimized the database structure and retrieval mechanism. With these improvements, we anticipate that G4LDB 2.2 will serve as a comprehensive resource and useful research toolkit for researchers across wide scientific communities and accelerate discovering and validating better binders and drug candidates.

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Bazoobandi, Mohadeseh, Mohammad R. Bozorgmehr, Ali Mahmoudi, and Ali Morsali. "The Effect of Temperature on the Interaction of Phenanthroline-based Ligands with G-quadruplex: In Silico Viewpoint." Combinatorial Chemistry & High Throughput Screening 22, no. 8 (December 19, 2019): 546–54. http://dx.doi.org/10.2174/1386207322666191022142629.

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Aim and Objective: The stability of the G-quadruplex structure can increase its activity in telomerase inhibiting cancer cells. In this study, a molecular dynamics simulation method was used to study the effect of three phenanthroline-based ligands on the structure of G-quadruplex at the temperatures of 20, 40, 60 and 80°C. Materials and Methods: RMSD values and frequency of calculated RMSD in the presence and absence of ligands show that ligands cause the relative stability of the G-quadruplex, particularly at low temperatures. The calculation of hydrogen bonds in Guanine-tetrads in three different quadruplex sheets shows that the effect of ligands on the sheets is not the same so that the bottom sheet of G-quadruplex is most affected by the ligands at high temperatures, and the Guaninetetrads in this sheet are far away. Conformation factor was calculated as a measure of ligands binding affinity for each of the G-quadruplex residues. Results: The results show that the studied ligands interact more with the G-quadruplex than loop areas, although with increasing temperature, the binding area also includes the G-quadruplex sheets. The contribution of each of the residues involved in the G-quadruplex binding area with ligands was also calculated. Conclusion: The calculations performed are consistent with the previous experimental observations that can help to understand the molecular mechanism of the interaction of phenanthroline and its derivatives with quadruplex.

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Kanti Si, Mrinal, Anik Sen, and Bishwajit Ganguly. "Exploiting hydrogen bonding interactions to probe smaller linear and cyclic diamines binding to G-quadruplexes: a DFT and molecular dynamics study." Physical Chemistry Chemical Physics 19, no. 18 (2017): 11474–84. http://dx.doi.org/10.1039/c7cp00472a.

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Głuszyńska, Agata, and Bernard Juskowiak. "Practical Microwave Synthesis of Carbazole Aldehydes for the Development of DNA-Binding Ligands." Molecules 24, no. 5 (March 9, 2019): 965. http://dx.doi.org/10.3390/molecules24050965.

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Microwave formylation of carbazole derivatives was investigated and 3-monoaldehydes were obtained in high yield. A potential DNA-binding ligand, 3-[(3-ethyl)-2-vinylbenzothiazolium]-9-N-ethyl carbazole iodide, was synthesized and characterized including spectral properties (UV-Vis absorption and fluorescence spectra). The binding selectivity and affinity of three carbazole ligands for double-stranded and G-quadruplex DNA structures were studied using a competitive dialysis method in sodium- and potassium-containing buffer solutions.

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Lauria, Antonino, Gabriele La Monica, Alessio Terenzi, Giuseppe Mannino, Riccardo Bonsignore, Alessia Bono, Anna Maria Almerico, Giampaolo Barone, Carla Gentile, and Annamaria Martorana. "Antiproliferative Properties and G-Quadruplex-Binding of Symmetrical Naphtho[1,2-b:8,7-b’]dithiophene Derivatives." Molecules 26, no. 14 (July 16, 2021): 4309. http://dx.doi.org/10.3390/molecules26144309.

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Background: G-quadruplex (G4) forming sequences are recurrent in telomeres and promoter regions of several protooncogenes. In normal cells, the transient arrangements of DNA in G-tetrads may regulate replication, transcription, and translation processes. Tumors are characterized by uncontrolled cell growth and tissue invasiveness and some of them are possibly mediated by gene expression involving G-quadruplexes. The stabilization of G-quadruplex sequences with small molecules is considered a promising strategy in anticancer targeted therapy. Methods: Molecular virtual screening allowed us identifying novel symmetric bifunctionalized naphtho[1,2-b:8,7-b’]dithiophene ligands as interesting candidates targeting h-Telo and c-MYC G-quadruplexes. A set of unexplored naphtho-dithiophene derivatives has been synthesized and biologically tested through in vitro antiproliferative assays and spectroscopic experiments in solution. Results: The analysis of biological and spectroscopic data highlighted noteworthy cytotoxic effects on HeLa cancer cell line (GI50 in the low μM range), but weak interactions with G-quadruplex c-MYC promoter. Conclusions: The new series of naphtho[1,2-b:8,7-b’]dithiophene derivatives, bearing the pharmacophoric assumptions necessary to stabilize G-quadruplexes, have been designed and successfully synthesized. The interesting antiproliferative results supported by computer aided rational approaches suggest that these studies are a significant starting point for a lead optimization process and the isolation of a more efficacious set of G-quadruplexes stabilizers.

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Granotier, C. "Preferential binding of a G-quadruplex ligand to human chromosome ends." Nucleic Acids Research 33, no. 13 (July 21, 2005): 4182–90. http://dx.doi.org/10.1093/nar/gki722.

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Huang, Yu Chuan, Katherine J. Castor, Hanadi F. Sleiman, and Dipankar Sen. "Mechatronic DNA devices driven by a G-quadruplex-binding platinum ligand." Bioorganic & Medicinal Chemistry 22, no. 16 (August 2014): 4376–83. http://dx.doi.org/10.1016/j.bmc.2014.05.023.

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Jin, Yan, and Yunxia Qiao. "A label-free method for identifying electroactive G-quadruplex-binding ligand." Electrochemistry Communications 12, no. 7 (July 2010): 966–69. http://dx.doi.org/10.1016/j.elecom.2010.05.003.

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Journal articles on the topic 'G quadruplex binding ligand'

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