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Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes
Open AccessArticle

Targeting G-quadruplexes with Organic Dyes: Chelerythrine–DNA Binding Elucidated by Combining Molecular Modeling and Optical Spectroscopy

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Institute of Inorganic Chemistry, University of Vienna, Währingerstrasse 42, A-1090 Vienna, Austria
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Donostia International Physics Center, Paseo Manuel de Lardizabal 4, 20018 Donostia, Spain
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Université de Lorraine and CNRS, LPCT UMR 7019, F54000 Nancy, France
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CNR-IOM DEMOCRITOS c/o International School for Advanced Studies (SISSA), 34136 Trieste, Italy
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Laboratoire International Associé Centre National de la Recherche Scientifique et University of Illinois at Urbana−Champaign, Urbana, IL 61820, USA
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Department of Physics, University of Illinois at Urbana−Champaign, 1110 West Green Street, Urbana, IL 61801, USA
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Dipartimento di Scienze Biologiche, Chimiche e Farmaceutiche, Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy
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Authors to whom correspondence should be addressed.
Antioxidants 2019, 8(10), 472; https://doi.org/10.3390/antiox8100472
Received: 7 September 2019 / Revised: 5 October 2019 / Accepted: 7 October 2019 / Published: 10 October 2019
(This article belongs to the Special Issue Oxidative Stress, DNA Damage and Biological Clinical Effects)
The DNA-binding of the natural benzophenanthridine alkaloid chelerythrine (CHE) has been assessed by combining molecular modeling and optical absorption spectroscopy. Specifically, both double-helical (B-DNA) and G-quadruplex sequences—representative of different topologies and possessing biological relevance, such as telomeric or regulatory sequences—have been considered. An original multiscale protocol, making use of molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, allowed us to compare the theoretical and experimental circular dichroism spectra of the different DNA topologies, readily providing atomic-level details of the CHE–DNA binding modes. The binding selectivity towards G-quadruplexes is confirmed by both experimental and theoretical determination of the binding free energies. Overall, our mixed computational and experimental approach is able to shed light on the interaction of small molecules with different DNA conformations. In particular, CHE may be seen as the building block of promising drug candidates specifically targeting G-quadruplexes for both antitumoral and antiviral purposes. View Full-Text
Keywords: guanine quadruplexes; anticancer drugs; all atom molecular dynamics; circular dichroism guanine quadruplexes; anticancer drugs; all atom molecular dynamics; circular dichroism
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MDPI and ACS Style

Terenzi, A.; Gattuso, H.; Spinello, A.; Keppler, B.K.; Chipot, C.; Dehez, F.; Barone, G.; Monari, A. Targeting G-quadruplexes with Organic Dyes: Chelerythrine–DNA Binding Elucidated by Combining Molecular Modeling and Optical Spectroscopy. Antioxidants 2019, 8, 472.

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