In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Kang, Hong Je; Park, Hyun-Ju

doi:10.1007/s10822-014-9826-z

Cited by 14 publications

(27 citation statements)

References 49 publications

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“…[274][275][276][277] Docking studies have used a range of large in silico libraries, with the ZINC and ChemBridge databases employed, for example, to find hits against the c-MYC quadruplexes. 280,281 Fragment-based design has not yet been used to full develop a novel lead compound, although a study using a fragment library derived from RNA-targeting has identified the potential of this approach. 282 Data from X-ray crystallography 35 and 2D-NMR studies 36 opportunities for ligand refinement and improvement.…”

Section: Ligand Designmentioning

confidence: 99%

Quadruplex Nucleic Acids as Novel Therapeutic Targets

2016

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Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters, and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be effectively resolved by helicase action. Mutated helicases in cancer cells are unable to unwind quadruplexes, which are impediments to transcription, translation, or replication, depending on their location within a particular gene. Small molecules that can stabilize quadruplex structures augment these effects and produce cell and proliferation growth inhibition. This article surveys the chemical biology of quadruplexes. It critically examines the major classes of quadruplex-binding small molecules that have been developed to date and the various approaches to discovering selective agents. The challenges of requiring (and achieving) small-molecule targeted selectivity for a particular quadruplex are discussed in relation to the potential of these small molecules as clinically useful therapeutic agents.

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Section: Ligand Designmentioning

confidence: 99%

Quadruplex Nucleic Acids as Novel Therapeutic Targets

2016

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“…The molecular structures of the c-MYC G-quadruplex and its drug complexes have been determined by solution NMR 24,28,29 . New G-quadruplex-interactive ligands with micromolar activities 30–33 have been identified in recent studies using the NMR structures of apo and ligand-bound c-MYC G-quadruplex molecules.…”

Section: Introductionmentioning

confidence: 99%

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

et al. 2017

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We report the absolute binding free energy calculation and surface plasmon resonance (SPR) experiment for ligand binding with the cMYC G-quadruplex DNA. The unimolecular parallel DNA G-quadruplex formed in the nuclease hypersensitivity element III1 of the c-MYC gene promoter regulates the c-MYC transcription and is recognized as an emerging drug target for cancer therapy. Quindoline derivatives have been shown to stabilize the G-quadruplex and inhibit the c-MYC expression in cancer cells. NMR revealed two binding sites located at the 5′ and 3′ termini of the G-quadruplex. Questions about which site is more favored and the basis for the ligand-induced binding site formation remain unresolved. Here, we employ two absolute binding free energy methods, the double decoupling and the potential of mean force methods, to dissect the ligand binding specificity in the c-MYC G-quadruplex. The calculated absolute binding free energies are in general agreement with the SPR result and suggest that the quindoline has a slight preference for the 5′ site. The flanking residues around the two sites undergo significant reorganization as the ligand unbinds, which provides evidence for ligand-induced binding pocket formation. The results help interpret experimental data and inform rational design of small molecules targeting the c-MYC G-quadruplex.

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“… 43 It was built over the template of the NMR solution structure (PDB-ID 2A5P) 25 using Maestro 45 and further details are as documented previously. 43 On the basis of the information provided in the literature, 23 , 25 , 28 , 43 the 5′ end of Pu27 was taken as the ligand binding site. A grid with an inner box (10 Å) and an outer box (30 Å) was built at the 5′ end of the quadruplex structure.…”

Section: Methodsmentioning

confidence: 99%

“… 17 − 22 Natural compounds and some synthetic chemical compounds have been studied for their stabilization effect on the G-quadruplex structure of Pu27 and the further inhibition of expression of the c-MYC oncogene. 23 − 30 Quarfloxin is the only quadruplex binding agent that has entered phase II clinical trials for its anticancer activity; 31 it was also found to inhibit c-MYC expression by binding to Pu27 . 32 Other chemical entities have been found to be transcriptional inhibitors of c-MYC through quadruplex interaction such as the perylene derivative PIPER ( N , N ′-bis(2-(1-piperidino)ethyl)-3,4,9,10-perylenetetracarboxylic acid diimide), 33 the cationic porphyrine derivative TmPyP4, 34 , 35 acridine derivatives, 36 quindoline derivatives, 27 , 37 the FDA-approved drug, methylene blue, 38 and so forth.…”

Section: Introductionmentioning

confidence: 99%

In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

et al. 2017

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Overexpression of c-MYC oncogene is associated with cancer pathology. Expression of c-MYC is regulated by the G-quadruplex structure formed in the G-rich segment of nuclease hypersensitive element (NHE III1), that is, “Pu27”, which is localized in the promoter region. Ligand-induced stabilization of the Pu27 structure has been identified as a novel target for cancer therapeutics. Here, we have explored the library of synthetic compounds against the predefined binding site of Pu27. Three compounds were selected based on the docking analyses; they were further scrutinized using all atom molecular dynamics simulations in an explicit water model. Simulated trajectories were scrutinized for conformational stability and ligand binding free energy estimation; essential dynamic behavior was determined using principal component analysis. One of the molecules, “TPP (1-(3-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-2-hydroxypropyl)-4-carbamoylpiperidinium)”, with the best results was considered for further evaluation. The theoretical observations are supported well by biophysical analysis using circular dichroism, isothermal titration calorimetry, and high-resolution NMR spectroscopy indicating association of TPP with Pu27. The in vitro studies were then translated into c-MYC overexpression in the T47D breast cancer cell line. Biological evaluation through the MTT assay, flow cytometric assay, RT-PCR, and reporter luciferase assay suggests that TPP downregulates the expression of c-MYC oncogene by arresting its promoter region. In silico and in vitro observations cumulatively suggest that the novel skeleton of TPP could be a potential anticancer agent by stabilizing the G-quadruplex formed in the Pu27 and consequently downregulating the expression of c-MYC oncogene. Derivation of new molecules on its skeleton may confer anticancer therapeutics for the next generation.

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In silico identification of novel ligands for G-quadruplex in the c-MYC promoter

Cited by 14 publications

References 49 publications

Quadruplex Nucleic Acids as Novel Therapeutic Targets

Quadruplex Nucleic Acids as Novel Therapeutic Targets

Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment

In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

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