title: Mechanistic insight into ligand binding to G-quadruplex DNA.
abstract: Specific guanine-rich regions in human genome can form higher-order DNA structures called G-quadruplexes, which regulate many relevant biological processes. For instance, the formation of G-quadruplex at telomeres can alter cellular functions, inducing apoptosis. Thus, developing small molecules that are able to bind and stabilize the telomeric G-quadruplexes represents an attractive strategy for antitumor therapy. An example is 3-(benzo[d]thiazol-2-yl)-7-hydroxy-8-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-2H-chromen-2-one (compound 1: ), recently identified as potent ligand of the G-quadruplex [d(TGGGGT)]4 with promising in vitro antitumor activity. The experimental observations are suggestive of a complex binding mechanism that, despite efforts, has defied full characterization. Here, we provide through metadynamics simulations a comprehensive understanding of the binding mechanism of 1: to the G-quadruplex [d(TGGGGT)]4. In our calculations, the ligand explores all the available binding sites on the DNA structure and the free-energy landscape of the whole binding process is computed. We have thus disclosed a peculiar hopping binding mechanism whereas 1: is able to bind both to the groove and to the 3' end of the G-quadruplex. Our results fully explain the available experimental data, rendering our approach of great value for further ligand/DNA studies.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego, 30, I-16163 Genoa, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano, 49, I-80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego, 30, I-16163 Genoa, Italy Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Belmeloro, 6, I-40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, and Facoltà di Informatica, Istituto di Scienze Computazionali, Università della Svizzera Italiana, via G. Buffi, 13, CH-6900 Lugano, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano, 49, I-80131 Naples, Italy vittoriolimongelli@gmail.com.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
mesh_terms: D001578:Benzopyrans / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry*; D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: D001578:Benzopyrans; D052160:Benzothiazoles; D008024:Ligands; D004247:DNA
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