Looking for Efficient G‐Quadruplex Ligands: Evidence for Selective Stabilizing Properties and Telomere Damage by Drug‐Like Molecules

Pagano, Bruno; Amato, Jussara; Iaccarino, Nunzia; Cingolani, Chiara; Zizza, Pasquale; Biroccio, Annamaria; Novellino, Ettore; Randazzo, Antonio

doi:10.1002/cmdc.201402552

Cited by 48 publications

(45 citation statements)

References 53 publications

(34 reference statements)

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“…The concentration of oligonucleotide solutions was determined by UV adsorption measurements at 90 °C using the appropriate molar extinction coefficient value ε ( λ = 260 nm) calculated by the nearest-neighbor model (83). Parallel G4 arrangement of telomeric DNA sequence was prepared and checked as previously described (84). Berberine chloride was purchased from Sigma-Aldrich and used without any further purification.…”

Section: Methodsmentioning

confidence: 99%

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Moraca

Amato

Ortuso

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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102

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SignificanceA thorough characterization of the binding interaction between a drug and its molecular target is fundamental to successfully lead drug design. We demonstrate that this characterization is also possible using the recently developed method of funnel-metadynamics (FM), here applied to investigate the binding of berberine to DNA G-quadruplex. We computed a quantitatively well-characterized free-energy landscape that allows identifying two low-energy ligand binding modes and the presence of higher energy prebinding states. We validated the accuracy of our calculations by steady-state fluorescence experiments. The good agreement between the theoretical and experimental binding free-energy value demonstrates that FM is a most reliable method to study ligand/DNA interaction.

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Section: Methodsmentioning

confidence: 99%

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Moraca

Amato

Ortuso

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

102

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“…Several organic molecules have been shown to be able to bind and stabilize BCL2 ‐G4 with subsequent down‐regulation of Bcl‐2 transcription and expression levels, thereby demonstrating the real potential of the G‐quadruplex‐targeting therapeutic approach, which also has the great advantage of circumventing the problem of acquired resistance, which is the main limitation of current Bcl‐2‐targeted therapeutic strategies. Most of the BCL2 ‐G4 ligands identified so far are characterized by a large, planar aromatic core with the capability of stacking on the external G‐tetrads, a common element in G‐quadruplex recognition . Therefore, although these ligands have shown good G‐quadruplex over duplex selectivity, they do not exhibit specificity for BCL2 ‐G4 versus other G‐quadruplex structures.…”

Section: Figurementioning

confidence: 99%

“…Most of the BCL2-G4 ligands identified so far are characterized by al arge, planar aromatic core with the capabilityo fs tacking on the externalG -tetrads, ac ommon elementi nG -quadruplex recognition. [13][14][15] Therefore, althought hese ligands have shown good G-quadruplex over duplex selectivity,t hey do not exhibit specificity for BCL2-G4 versus other G-quadruplexs tructures. Moreover,m ost of them share unfavorable chemical properties such as high molecular weight and/or hydrophobic nature,w hich result in very poor drug-like properties.…”

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confidence: 99%

Targeting the BCL2 Gene Promoter G‐Quadruplex with a New Class of Furopyridazinone‐Based Molecules

et al. 2018

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Targeting of G-quadruplex-forming DNA in the BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein is an attractive approach to cancer treatment. So far, efforts made in the discovery of molecules that are able to target the BCL2 G-quadruplex have succeeded mainly in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity. Moreover, one such ligand was found to appreciably inhibit BCL2 gene transcription, with a substantial decrease in protein expression levels, and also showed significant cytotoxicity toward the Jurkat human T-lymphoblastoid cell line.

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“…In many cases, quadruplex DNA is a less efficient substrate for polymerase than double‐stranded DNA . Much effort has been devoted to the development of efficient ligands that bind telomeric DNA and strongly stabilize the GQ structure over the double‐stranded form and, therefore, serve as indirect telomerase inhibitors with potential applications in antitumor therapy …”

Section: Introductionmentioning

confidence: 99%

Weak Supramolecular Interactions Governing Parallel and Antiparallel DNA Quadruplexes: Insights from Large‐Scale Quantum Mechanics Analysis of Experimentally Derived Models

Yurenko

Novotný

Marek

2017

Chemistry A European J

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The topology and energetics of guanine (G) quadruplexes is governed by supramolecular interactions within their strands. In this work, an extensive quantum mechanical (QM) study has been performed to analyze supramolecular interactions that shape the stems of (4+0) parallel (P) and (2+2) antiparallel (AP) quadruplex systems. The large-scale (≈400 atoms) models of P and AP were constructed from high-quality experimental structures. The results provide evidence that each of the P and AP structures is shaped by a distinct network of supramolecular interactions. Analysis of electron topological characteristics of hydrogen bonds in P and AP systems indicates that the P model benefits from stronger intratetrad hydrogen bonding. For intertetrad stacking interactions, both noncovalent interaction plot and energy decomposition analysis approaches suggest that the stem of the P quadruplex benefits more from stacking than that of the AP stem; the difference in energetic stabilization for the two topologies is about 10 %. Stronger hydrogen-bonding and stacking interactions in the stem of the P quadruplex, relative to those in the AP system, can be an important indicator to explain the experimental observations that guanine-rich oligonucleotides tend to form all-parallel stems with an all-anti orientation of nucleobases. However, in addition to intrinsic stabilization, partial desolvation effects, which affect the energetics and dynamics of the G-quadruplex folding process, call for further investigations.

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Looking for Efficient G‐Quadruplex Ligands: Evidence for Selective Stabilizing Properties and Telomere Damage by Drug‐Like Molecules

Cited by 48 publications

References 53 publications

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

Targeting the BCL2 Gene Promoter G‐Quadruplex with a New Class of Furopyridazinone‐Based Molecules

Weak Supramolecular Interactions Governing Parallel and Antiparallel DNA Quadruplexes: Insights from Large‐Scale Quantum Mechanics Analysis of Experimentally Derived Models

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