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Molecules 2018, 23(9), 2266; https://doi.org/10.3390/molecules23092266

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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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)
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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 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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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