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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

Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India
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Author to whom correspondence should be addressed.
Academic Editor: Danzhou Yang
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
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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. View Full-Text
Keywords: daunomycin; G-quadruplex DNA; surface plasmon resonance; circular dichroism; nuclear magnetic resonance; intermolecular NOEs; restrained molecular dynamics simulations; differential scanning calorimetry; thermal stabilization daunomycin; G-quadruplex DNA; surface plasmon resonance; circular dichroism; nuclear magnetic resonance; intermolecular NOEs; restrained molecular dynamics simulations; differential scanning calorimetry; thermal stabilization
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Barthwal, R.; Tariq, Z. 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, 2266.

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